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Review

Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases

by
Sungtae Yoon
1,
Gyeongyun Go
2,3,
Yeomin Yoon
4,
Jiho Lim
4,
Gaeun Lee
2,3 and
Sanghun Lee
1,2,3,4,*
1
Stembio, Ltd., Entrepreneur 306, Soonchunhyang-ro 22, Sinchang-myeon, Asan 31538, Korea
2
Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 31151, Korea
3
Department of Biochemistry, BK21FOUR Project2, College of Medicine, Soonchunhyang, Cheonan 31151, Korea
4
Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea
*
Author to whom correspondence should be addressed.
Biomolecules 2021, 11(6), 784; https://doi.org/10.3390/biom11060784
Submission received: 29 April 2021 / Revised: 18 May 2021 / Accepted: 19 May 2021 / Published: 22 May 2021
(This article belongs to the Special Issue Prions and Prion-Like Mechanisms in Disease and Biological Function)
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Abstract

:
A cellular prion protein (PrPC) is a ubiquitous cell surface glycoprotein, and its physiological functions have been receiving increased attention. Endogenous PrPC is present in various kidney tissues and undergoes glomerular filtration. In prion diseases, abnormal prion proteins are found to accumulate in renal tissues and filtered into urine. Urinary prion protein could serve as a diagnostic biomarker. PrPC plays a role in cellular signaling pathways, reno-protective effects, and kidney iron uptake. PrPC signaling affects mitochondrial function via the ERK pathway and is affected by the regulatory influence of microRNAs, small molecules, and signaling proteins. Targeting PrPC in acute and chronic kidney disease could help improve iron homeostasis, ameliorate damage from ischemia/reperfusion injury, and enhance the efficacy of mesenchymal stem/stromal cell or extracellular vesicle-based therapeutic strategies. PrPC may also be under the influence of BMP/Smad signaling and affect the progression of TGF-β-related renal fibrosis. PrPC conveys TNF-α resistance in some renal cancers, and therefore, the coadministration of anti-PrPC antibodies improves chemotherapy. PrPC can be used to design antibody–drug conjugates, aptamer–drug conjugates, and customized tissue inhibitors of metalloproteinases to suppress cancer. With preclinical studies demonstrating promising results, further research on PrPC in the kidney may lead to innovative PrPC-based therapeutic strategies for renal disease.

1. General Characteristics of Cellular Prion Proteins in Kidneys

A cellular prion protein (PrPC) is a glycoprotein on the cell surface. This particular protein has drawn extensive attention and investigation since it was first proposed that infective misfolded PrPC could be responsible for various neurodegenerative disorders that are often referred to as transmissible spongiform encephalopathies (TSEs) or, more commonly, prion disease [1,2]. There is a growing body of evidence that suggests that cellular prion proteins are involved in various cellular processes, and alterations in PrPC expression can result in significant changes in cellular physiology [3,4,5]. PrPC is found in various organs and systems [6], but detailed characterization of the extra-neuronal roles of PrPC has trailed behind [7]. In this review, we provide an overview of the functions of PrPC in the kidneys and examine the experimental strategies involving PrPC to treat kidney diseases.
It has been well-documented that PrPC exists in two distinct conformations: first, the host-encoded cellular prion protein that carries out the normal physiological functions (PrPC), and second, the misfolded infective isoform that is often called pathogenic prion protein (usually denoted as PrPSc) [7]. PrPC is encoded by the PRNP gene located on chromosome 20 in humans and chromosome 2 in mice (Prnp) [8]. Translation of the PRNP gene results in the production of PrPC, which undergoes post-translational modification to reach the mature polypeptide comprised of 208 amino acids (Figure 1A). PrPC is anchored to the outer leaflet of the cellular membrane through its connection to glycosylphosphatidylinositol (GPI). Two short antiparallel beta sheet strands and three alpha helices of the C-terminus contribute to the overall structure of PrPC, while its pathogenic misfolding (or PrPC-to-PrPSc conversion) could lead to an alternative conformation with a high beta sheet content (Figure 1B). It is important to note that the representation of the PrPSc structure in this article corresponds to the 4-rung beta-solenoid (4RβS) model of PrPSc [9], which is one of the more accepted provisory models for illustrating the prion protein structure, as no definitive answers have been given to the structure of PrPSc. There is an ongoing debate on the existence of the third beta sheet (not shown in our illustration) in the PrPC structure, which may have role in PrPC-to-PrPSc conversion [3]. Interestingly, PrPC may undergo further modifications with proteolytic processing at the central region, the C-terminus, or GPI anchor to achieve several different isoforms of PrPC [10].
PrPC is taken up and cleared by the kidney [11]. Two in situ hybridization studies found high levels of PrPC mRNA in kidneys [12,13], while a different article reported a moderate PrPC mRNA expression [14]. PrPC is abundantly expressed and selectively present in podocytes, which constitutes the epithelial lining around glomerular capillaries and their neighboring extraglomerular mesangial cells in the Bowman’s capsule [15]. Endogenous PrPC are present in the proximal convoluted tubules, medullary collecting ducts, renal extraglomerular mesangial cells (EMC), podocytes, and endothelial cells (Figure 1C), as confirmed with mapping of the PrPC protein expression through immunohistochemistry and the quantification of PrPC via Western blotting [16]. Interestingly, the level of PrPC in the kidney seems to vary depending on the age of the subject animal [15] and tissue type [17,18]. In a similar vein, there seems to be a temporal aspect to changes in the PrPC mRNA levels [19,20], and the isoform profile of PrPC was observed to be tissue-specific [14,21]. These observations suggest that delineating the functions of PrPC may require cross-validation across different tissue types.
Abnormal prion proteins (or prion) are detected in the kidneys affected by prion disease (Figure 1D). Creutzfeldt-Jakob disease (CJD) is a fatal prion disease that presents with rapidly progressive dementia [22], and prion proteins were found in the kidneys and urine of sporadic CJD (sCJD) patients [23]. Protease-resistant variants of the prion protein were found in the kidneys of patients affected by variant CJD (vCJD) [24]. In chronic wasting disease (CWD), another prion disease affecting cervids, the immunolabeling of infective prion proteins consistently stains arterial vessels, the wall of the main renal artery, arcuate arteries at the junction of the renal cortex and renal medulla, and renal glomeruli [25]. Scrapie-affected sheep have pathological prion proteins (PrPSc) deposited at the intraepithelial and interstitial tissues of the kidney [26]. Some of these prion proteins detected in the kidneys arrive through the blood circulation for glomerular filtration [11], while others are generated by the kidneys themselves [14]. Prion proteins are filtered into urine [27], and urinary prion proteins could be a source of prion disease infection [28,29] or serve as a biomarker for a noninvasive diagnosis of prion disease [30]. For example, in sCJD patients, prion seeding activities occurs in the kidney as a result of infective prions flowing out from the central nervous system and infecting kidneys and adrenal glands to produce pathological prion proteins onsite [31]. The detection of these disease-related prion proteins via urine screening is suggested as a novel method for diagnosing sCJD [32].
The general functions of PrPC have been extensively investigated via gene knockout experiments. The putative functions associated with PrPC (Figure 2A) include the stress response [33,34,35,36], providing protective effects against oxidative stress [37,38,39], cellular differentiation [40,41,42], neuronal excitability [43,44,45], myelin maintenance [46,47,48], circadian rhythm [49,50], metal ion homeostasis [51,52,53], modulation of the immune system [54], the regulation of amyloid beta and tau protein [55], control of the cellular signaling pathways [56,57], and a few other common cellular processes [7]. Since PrPC downregulation occurs during the disease incubation period [58], the loss of normal PrPC function may partly underlie the pathology of prion protein-related diseases, and PrPC could be targeted for therapeutic purposes. There is evidence for the PrPC-mediated suppression of apoptotic signals [59] via TNF [60], BAX [61], or caspase-dependent [62] pathways. The PrPC level is altered in ischemic and hypoxic injury [63], and the severity of the ischemic injury was reduced with the adenovirus-mediated promotion of PrPC [64] but aggravated when PrPC was absent [65].
With the expanding understanding of normal PrPC functions, renal PrPC is becoming an increasingly relevant factor for renal physiology and pathophysiology. In the past, PrPC in kidney tissues has been only used as a proxy model for studying neuronal PrPC [66], which led to the current unavailability of literature dedicated towards examining the functions of PrPC in the kidneys. Given that recent studies on kidney injuries and PrPC have demonstrated that PrPC could be a reliable biomarker for renal injury [67] and protect cells against a chronic kidney disease (CKD) environment [68], further exploration of the link between various kidney diseases and endogenous PrPC is greatly merited. Throughout this review, we have summarized the current understandings of PrPC in the kidneys and its application in renal pathologies and identified potential PrPC-based therapeutic strategies for major kidney diseases, including acute and chronic kidney injury, renal fibrosis, and cancers.

2. Physiological Functions of PrPC in the Kidneys

Over the course of the past couple of decades, endogenous PrPC has been linked to a wide array of cellular processes with many interacting partners [7], but not many of the putative functions of PrPC with respect to neuronal tissues have been tested or confirmed specifically for their relevance in renal physiology. Nevertheless, the similarities between neurons and certain kidney cells allows for the speculation that some of the endogenous PrPC functions observed in neurons may also remain present in the kidney environment [66]. For example, renal glomerular podocytes have major processes that share important cellular characteristics with neuronal dendrites, and these two types of cells share similar expressions of various molecules involved in signal transduction, trans-membranous transport, and intercellular contacts [69].
The synaptic-like mechanism of communication among glomerular cells also significantly resembles neurons [70], and some iconic neuronal proteins are not only expressed but also play a significant role in the formation and function of renal podocyte processes [71]. The recognition of these similarities motivated the further studying of cellular prion proteins in the kidneys, which led to the discovery that PrPC is present in many kidney tissues, including podocytes [15,16], as discussed previously. Further investigation is needed to verify whether the aforementioned similarities help cellular prion proteins carry out in the kidneys some of the functions PrPC exhibit in neurons. In this section, we highlighted some of the functions of PrPC as they are supported by the currently available in vitro and in vivo data related to the kidneys.

2.1. PrPC Regulates Renal Cellular Signaling

A combination of PrPC and its diverse interacting partners can initiate a variety of downstream cellular signaling pathways (Figure 2A). Several review articles have gathered experimental evidence across different experimental models for the PrPC-mediated regulation of the ERK1/2 [72,73,74], PI3K/Akt [74,75,76,77], cAMP/PKA [72,78], Fyn kinase (Src family kinase) [79,80], RhoA/ROCK [81], and PKC [74] transduction pathways. It is noteworthy that, except for the ubiquitous effectors, many PrPC-mediated signaling pathways have neurospecificity [82], and the complex crosstalk networks between the major signal transduction pathways pose a significant challenge for identifying the direct effectors of PrPC. In addition, the context-dependent regulation of signal transduction implies that many of these PrPC-mediated pathways may result in different or even contradictory outcomes in different tissues or cell types [7]. Therefore, we focused on the documented cases of PrPC-mediated regulation of cellular signaling as they are verified in renal cells or kidney tissues.
Extracellular signal-regulated kinases 1/2 (ERK1/2) are some of the best characterized kinases within the mitogen-activated protein kinase (MAPK) family, and ERK1/2 are activated via phosphorylation (pERK) after the incidence of ischemia/reperfusion injury [83,84] to exercise a protective effect [85,86]. In this case, PrPC prevents the cellular damage caused by an overdrive of ERK activity [87,88]. A more detailed look at the temporal changes in the pERK levels in PrPC knockout and wild-type mice upon renal injury led to interesting observations where the pERK levels continually and steadily increased from day 1 to day 3, while the pERK levels in PrPC-null mice showed a sudden spike on day 1, followed by a significant decline far below the wild-type level on day 2 and another more reasonable increase on day 3 [86]. The spike in pERK in PrPC knockout mice was observed mostly in the renal tubular cells, which means that the ERK pathway drove the renal tubular damage in the absence of PrPC [86]. These intriguing patterns of the PrPC deletion-associated pERK phenotype in kidney damage warrant further study, especially considering the strong potential of crosstalk between the different signaling modules. Other literature suggests the involvement of PrPC in the STAT1 pathway, AKT pathway, and caspase-3-mediated pathways [65,87], but these have not been directly verified for kidney tissues.
In addition, PrPC may act as the downstream effector of growth factor signaling in the kidneys. Proximal tubule epithelial cells (PTEC) undergo necrosis under renal ischemic insult, and the damage in the tubules and interstitium of the kidneys can be measured to assess the kidney function and renal health [89]. PTECs trigger an inflammatory response due to kidney injury by producing proinflammatory chemokines and cytokines, which could aggravate ischemic kidney disease [90]. Bone morphogenic protein-7 (BMP-7), which is part of the TGF-β superfamily, is known to play an important role in epithelial tubule development [91], and the expression of BMP-7 in adult kidneys was related to the decrease in the inflammatory response in kidney injuries [92,93,94]. In a rodent model, the direct administration of BMP-7 to the kidneys with renal ischemia led to the increased survival and decreased inflammatory damage of kidney tissues [95,96]. A gene array analysis used to identify the genes regulated by BMP-7 in primary human proximal tubule cells revealed that the major prion protein precursor gene showed an almost two-fold decrease in response to the BMP-7 treatment in the presence of proinflammatory cytokine TNF-α [97]. Although the protein-level expression of PrPC needs further validation, this data provides evidence that additional research may identify many other signaling pathways to either regulate or be modulated by PrPC in renal tissues.
Furthermore, the PrPC-dependent cellular signaling pathways could be modulated with certain small molecules and nucleic acids that act as upstream regulators of PrPC. Tauroursodeoxycholic acid (TUDCA) was found to induce the Akt-dependent PrPC signaling cascade to reduce ER stress-related cell death and to improve angiogenesis [98], and a treatment with pioglitazone inhibited apoptosis, ameliorated dysregulation in mitochondrial fusion and fission, and improved mitophagy via the PGC-1α/PrPC axis [99]. In addition, a melatonin treatment was found to promote miR-4516 to upregulate PrPC to improve the mitochondrial function [68]. The identification of the miR-4516/PrPC interaction in CKD suggests that there may be many other microRNAs acting upstream of PrPC to modulate the cellular processes in the kidneys. Recently, a genome-wide library screening of miRNA mimics reported several high-confidence hits for the regulation of human PrPC [100], and recognition for the importance of renal RNA and miRNA profiles in progressive kidney diseases is on the rise [101,102,103,104]. Different strategies to target PrPC-mediated renal cellular signaling with the purpose of designing and developing treatments for kidney disease are discussed in greater detail in later sections of this review.

2.2. PrPC Responds to Kidney Injury

The cellular prion protein has been associated with neuro-protective functions, and among them, protection against ischemic brain injury is one of the best-characterized roles of PrPC [85]. In the brain, hypoxic damage triggers PrPC mRNA upregulation and PrPC accumulation in a murine model [63] and human patients [105]. PrPC deficiency leads to greater infarction [63] through the ERK and STAT1 pathways [87] or Akt activation and post-ischemic caspase-3 activation [65], and the overexpressing PrPC via adenovirus-mediated gene targeting demonstrated reduced ischemic injury [64]. This is another PrPC function that is suspected to have broad applicability in other peripheral organs that are susceptible to ischemic injury.
In fact, when the murine PrPC gene was overexpressed in rabbit kidney epithelial cells and treated with a hydroxyl radical-generating chemical toxin (paraquat), the PrPC-overexpressed cells were found to have a significantly reduced chemical-induced cell toxicity, DNA damage, and lipid peroxidation, while demonstrating enhanced superoxide dismutase and glutathione peroxidase activities [106]. Subsequently, this protective role of PrPC was later confirmed in the heart [38], and this inspired a similar investigation for the kidney. Zhang et al. found that the PrPC levels were significantly increased upon ischemia/reperfusion injury (IR injury) in mice kidneys compared to the control kidney from healthy mice, and IR injury in PrPC knockout mice resulted in more severe tubular damage, worse renal dysfunction, increased oxidative stress markers, impaired mitochondrial respiratory chain functionality due to decreased expressions of complexes I and III, and enhanced phosphorylation of the ERK pathway compared to the wild-type control [86].
Taken together, there seems to be sufficient evidence for PrPC-mediated protection against renal IR injury, particularly through modulation of the mitochondrial function and the ERK signaling pathway (Figure 2B). This provides a plausible explanation for why PrPC is secreted by renal epithelial cells under endoplasmic reticulum stress [67]. The current efforts to take advantage of such protective functions of PrPC will be reviewed in the following sections.

2.3. PrPC Promotes Iron Uptake in the Kidneys

One of the few well-documented physiological functions of PrPC in the kidneys is its role in iron uptake (Figure 2C). Interestingly, the documentation of this effect was motivated by the convenience of using the kidney as a proxy model to study the dysregulation of iron homeostasis in the central nervous system. The alteration of iron homeostasis by the loss of PrPC-mediated conversion of Fe3+ reduction to Fe2+ has been speculated as an important cause of neurotoxicity in prion disorders [107], but a more detailed characterization of this model was carried out using in vivo and in vitro kidney models, where a PrPC-promoted uptake of transferrin- (Tf) and non-Tf-bound iron (NTBI) via ferrireductase activity in the kidneys was confirmed [66,108]. A ferrireductase-deficient mutant of PrP (PrPΔ51–89) lacked this activity [66], suggesting that PrPC promotes the retrieval of iron via its ferrireductase activity. Additional research unveiled the mechanism of such PrPC modulation of kidney iron metabolism: a cellular prion protein acts as a ferrireductase partner and regulator for divalent metal iron transporters ZIP14 and DMT1 [109,110].
PrPC modulation of the iron uptake is an example of how understanding of the PrPC function was improved through expanding the scope of a PrPC study beyond neuronal tissues. These results not only provided valuable data for studying neurodegenerative disease but also had more immediate applications for kidney disease. Iron homeostasis is critical for multiple physiological processes, and an imbalance in iron homeostasis has been associated with multiple pathological processes [111]. As the kidney plays a vital role in iron homeostasis through the renal reabsorption of iron ions [112,113], acquired or inherited disturbances in this process can cause systemic or local iron accumulation or iron deficiency, both of which lead to adverse pathological outcomes [114,115,116]. Therefore, targeting the iron homeostasis pathway may serve as a therapeutic target [117] to either prevent or delay progressive kidney diseases [118].

3. PrPC and Kidney Disease

The normal function and characteristics of PrPC functions, as mentioned in the previous sections, are implicated in some of the most common kidney diseases that are not classified as prion disease. The application of these properties to develop PrPC-based therapies may lead to innovative approaches that could compensate or overcome the limitations of the currently available treatment options for many kidney diseases, including acute kidney injury, chronic kidney disease, renal fibrosis, and renal cancer (Table 1). There are other kidney diseases like IgA nephropathy where the implication of PrPC processes have been suggested [119] but understanding of the underlying mechanism of endogenous PrPC involvement is absent. Therefore, taking advantage of the properties of PrPC to achieve clinical success is dependent on elucidating the exact roles of PrPC in the target disease.
Here, it could be appropriate to reiterate that the focus of this section is on the kidney diseases that may have pathogenic mechanisms involving alterations in the expression or functions of cellular prion proteins, rather than prion disease affecting kidney functions through the accumulation of abnormal prion proteins. The former does not generate infectious proteins, and PrPC is implicated as a modulator of important cellular processes relevant for the disease etiology [142]. Therefore, the altered PrPC levels we discuss in relation to chronic kidney disease are mostly unrelated to the transmissible misfolded PrPSc that is critical in prion disease.

3.1. PrPC and AKI/CKD

The kidneys play a critical role in maintaining the overall health of an individual by filtering toxic metabolic waste products [122] and maintaining adaptive tissue repair programs [67,143]. Compromised kidney functions often have multifactorial etiology [120,144,145,146,147,148,149], but they all progress towards chronic kidney disease (CKD), which is often diagnosed by a decreased glomerular filtration rate and persistently elevated levels of serum creatinine and albuminuria [143]. Acute kidney injury (AKI) has been formerly known as acute renal failure that affects many hospitalized patients and critically ill patients and is characterized by a rapid loss of the kidney’s excretory function, measured by the accumulation of nitrogen metabolism end products (urea and creatinine) [150]. Chronic kidney disease (CKD) has been defined by a reduced glomerular filtration rate and increased urinary albumin excretion for three months or longer [151]. AKI is very common among hospitalized patients, with mortality above 50% for critically ill patients [150]. CKD is affecting an increasingly higher number of people worldwide, with the global population aging very quickly, and CKD patients often led to premature deaths and a loss of disability-adjusted life years [151]. Renal replacement therapy is indicated for AKI and CKD without any effective cure [152,153].
Both AKI and CKD are heterogenous diseases with varying pathogenic mechanisms, and there is strong evidence suggesting that they are closely related, as CKD can both be a predisposition for AKI or result from recurrent or sustained AKI [154,155,156]. One of the most significant pathologic processes of kidney damage is renal ischemia/reperfusion injury (IRI), which is a common cause for AKI, and the subsequent transition into CKD [121,157,158,159,160]. As PrPC protects against renal IRI via its engagement with the ERK1/2 pathway [86], promoting this effect in the kidneys may lead to therapeutic outcomes. In fact, an overexpression of PrPC through adenovirus-mediated gene transfer reduced cerebral ischemic injury and improved neurological dysfunctions in rats [64,88]. Investigation into similar approaches for renal IRI is merited.
Another important factor in AKI and CKD is the iron level. Iron is known to be essential for the health and normal functioning of many tissues, including the kidneys but, specifically for CKD and AKI, iron dysregulation initiates of oxidative stress, mitochondrial dysfunction, and inflammation [118]. Glomerular and renal tubular cell injuries may increase the iron content in an intracellular space, and reducing these excessive luminal or intracellular iron levels in the kidneys has been proposed as a promising approach to treat AKI and CKD [115]. Since a prion protein (PrPC) functions as a ferrireductase at the apical side of the proximal tubule epithelial cells, and renal iron handling mechanisms differ from one nephron segment to another [66], we may speculate that some subset of AKI or CKD etiology may be based on disturbances in the PrPC function, and the identification of these subtypes may be helpful in delineating different causes of kidney failure to find better intervention strategies.
On a different note, PrPC may be useful for improving the therapeutic efficacy of autologous cell therapy for CKD. As the regenerative ability of the kidneys after injury is quite limited, the ability of MSCs to trigger regenerative processes, through paracrine activities [161] after migration to the injury site via the secretion of various growth factors and cytokines or extracellular vesicles filled with cell-to-cell signaling factors like microRNA, is of great interest for developing AKI or CKD treatments [162]. Recently, a systemic review and meta-analysis of preclinical studies on applying cell-based therapy for chronic kidney disease concluded that the use of mesenchymal stem/stromal cells (MSCs) was associated with the highest efficacy [163]. The injection of autologous adipose tissue-derived MSCs for the treatment of CKD was reported as clinically safe in a pilot study [164]. There have been quite a few clinical trials that have reached phase I or Phase II for MSC-based cell therapy for different types of CKDs, though no large-scale trial has been reported due to the difficulty associated with the mass production of qualified MSCs [165,166].
Despite the potential of MSCs for realizing personalized medicine, the viability of MSCs, and their capacity to induce regenerative processes, is greatly diminished when they are faced with an adverse renal microenvironment (including a hypoxic environment, proinflammatory condition, free radical-induced oxidative stress, etc.) at damaged tissues of diseased kidneys [167]. Therefore, enhancing the functionality and therapeutic efficacy of MCS-based cell therapy depends on providing adequate protection against the hostile microenvironment of injured kidneys for AKI and CKD patients [166]. There have been a lot of progress in elucidating the interaction between MSC and the microenvironment of the engraftment site, and this provides a new opportunity to engineer a therapeutic effect [127,168,169]. Controlling the growth condition is one common way to improve the functions of MSCs [127,166], and PrPC is a promising target for enhancing their therapeutic efficacy [170]. Some of the experimentally validated interventions to alter the growth conditions of MSCs to improve the PrPC-mediated protective effects are summarized below.
First, tauroursodeoxycholic acid (TUDCA), or bile acid, has been found to reduce the proteins associated with the damage from ischemia-induced endoplasmic reticulum (ER) stress in MSCs [98,171]. Investigation into the mechanism has revealed that TUDCA effectively protects MSCs through an Akt-dependent PrPC-signaling cascade in vivo and in vitro, while effectively reducing ER stress-related cell death and improving angiogenesis [98]. TUDCA–PrPC protection of MSCs has been verified with a P-cresol-induced CKD mice model. In the presence of the uremic toxin P-cresol, ROS-mediated ER stress increased cell death in SH-SY5Y cells, and a coculture with TUDCA-treated CKD-hMSCs increased the antioxidant enzyme activities in SH-SY5Y cells through upregulation of the PrPC expression, which was responsible for the observed protective effects against CKD-mediated ER stress and apoptosis [172].
Second, PrPC responds to treatment with melatonin, a pineal gland secretory hormone associated with the regulation of circadian rhythms and homeostasis [173]. When MSCs are pretreated with melatonin, they show an improved survival rate at the damaged tissues and demonstrate an increased capacity for improving angiogenesis, renal cell proliferation, and overall renal function, as measured by the decrease in plasma creatinine and urea [174]. Mitochondrial function was also improved in a PrPC-dependent manner in the CKD mice model with a melatonin pretreatment [175]. Instead of using melatonin directly on MSCs derived from CKD patients (CKD-MSCs), healthy MSCs can be utilized to produce exosomes with reno-protective signaling molecules. Treating healthy MSCs with melatonin increased the PrPC in exosomes isolated from MSCs through the upregulation of miR-4516 and, when CKD-MSCs are treated with these exosomes from melatonin-treated healthy MSCs, a significant increase in the levels of angiogenesis-associated proteins through miR-4516-PrPC signaling [68]. This approach seems to mitigate the challenge with the innate functional impairments of CKD-MSCs due to their adverse growth conditions caused by exposure to uremic toxins circulating in the body of CKD patients.
In this context, miR-4516 and PrPC augment the regenerative potential of MSCs and MSC-derived extracellular vehicles (EVs) for AKI or CKD treatments. This data is very informative for developing a therapeutic application of EVs for kidney disease. EVs are nanosized vesicles released by various cells and are known to participate in inter-nephron cellular communication [176,177]. The application of EVs as a therapeutic vector is becoming increasingly popular for renal disease [178,179,180], yet a wide variety of different combinations of source cells and effective molecules are still being tested to search for the best treatment regimen for CKD [181]. Mesenchymal stem cells [182,183], endothelial progenitor cells [184], and tubular epithelial cells [185] are some of the leading contenders for EV biogenesis, while using EVs loaded with either heterogeneous natural contents [186], small immunoregulatory proteins [187], or microRNAs [68,188,189], as effective molecules are yielding promising results in AKI- or CKD-related preclinical studies [181]. It is plausible that miR-4516 or PrPC could be employed as potent effective molecules to enhance EV-based therapies for kidney injuries.
Lastly, pioglitazone, an antidiabetic medication used to treat type 2 diabetes, also increases the expression of cellular prion proteins (PrPC) in CKD-MSCs. In one study, a pioglitazone treatment increased the expression levels of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which, in turn, upregulated the PrPC expression in CKD-MSCs. The activation of the PGC-1α/PrPC axis inhibited apoptosis, ameliorated dysregulation in mitochondrial fusion and fission, and improved mitophagy [99]. In a different study, this PrPC-mediated regulation of mitophagy was associated with the upregulation of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK-1) via nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) [190]. These data suggest that a pioglitazone treatment could be another way to improve the candidacy for MSCs for the cell-based treatment of kidney injuries.
As mentioned before, the infliction of a kidney injury in either AKI or CKD seems to alter the expression of endogenous PrPC in the kidneys. One study reported that the blood plasma obtained from 20 patients with renal failure showed higher levels of PrPC, which was not removed via hemodialysis [191]. However, an examination of the serum sample obtained from 37 CKD patients revealed that PrPC was significantly decreased in the CKD group [68]. This is consistent with our other subsequent studies of PrPC expression in the cells and tissues obtained from CKD patients [68,99,174]. This disagreement may be attributed to a number of factors. First, CKD patients often receive heparin during dialysis, which may impact the PrPC expression level [191]. The difference between the plasma and serum may have played a minor role as well. In addition, it has been suggested that the PrPC response observed in renal failure is not generalizable for different chronic illnesses or an acute phase reaction [191]. This suggests that the PrPC expression in AKI or CKD may vary from one subtype to another, since CKD and AKI are defined by their kidney function, not by the pathogenic factors responsible for renal failure. For example, CKD resulting from von Willebrand disease [192] have very different etiology from CKD with diabetes mellitus [120,123,124], so screening for CKD patients based on the glomerular filtration rate and high creatinine may overlook this confounding variable in characterizing the association between CKD and PrPC expressions. However, all of the studies examined in this review presented a statistically significant difference for the PrPC expressions between the kidneys of AKI or CKD patients and the healthy control groups. Taken together, we can conclude that PrPC dysregulation is implicated in AKI or CKD, but the detail of PrPC involvement awaits further clarification.

3.2. PrPC and Renal Cancer

There is evidence that PrPC contributes to the resistance against tumor necrosis factor α (TNF-α) apoptosis pathway in renal adenocarcinoma. PrPC-expressing renal adenocarcinoma cells (ACHN cells) demonstrated a modest but statistically significant increase in cell viability compared with the control group via the suppression of TNF-α-induced cell death, and the PrPC expression in ACHN led to a higher proliferative index [125]. This is interesting, because there is a large volume of research on how PrPC could mediate the tumorigenic effects and promote cancer proliferation, metastasis, drug resistance, and the cancer stem cell phenotype [34].
In our previous work, we confirmed the anticancer effects of the anti-prion antibody in a xenograft model and found that a cotreatment of anticancer drugs with the anti-prion antibody can achieve superior efficacy, with a much lower dosing of chemotherapeutic agents in colorectal cancer (unpublished data). In accordance with our findings, another literature on PrPC antibody treatment against colon cancer reported increased apoptosis via reduced Bcl-2 expression; antiproliferative activity; and enhanced effects of irinotecan, 5-FU, cisplatin, and doxorubicin in combination therapy [193].
Antibody–drug conjugates are another category of antibody-based therapeutics under active investigation for their application in cancer [126,194,195,196,197], and PrPC may serve as a potential target for antibody–drug conjugates [34]. Here, aptamers, which are oligonucleotides or peptides that bind to specific target molecules, can be used in lieu of antibodies to create another targeted drug delivery system called aptamer–drug conjugates, as aptamers have a few distinctive advantages over antibodies for their engineering simplicity, rapid tissue penetration, and low immunogenicity [198,199,200]. We previously synthesized PrPC aptamer (Apt)-conjugated gold nanoparticles (AuNPs) for the targeted delivery of doxorubicin, which induced reactive oxygen species generation in colorectal cancer cells by decreasing the catalase and superoxide dismutase activities [128]. Given these discoveries in various cancer types, the conjugation of drugs to either the PrPC antibody or PrPC aptamer may be an effective way to improve drug delivery for kidney cancers.
While a majority of the efforts to take advantage of PrPC in therapeutic development focuses on the regulatory role of PrPC in cellular processes, the properties of PrPC as a cell surface protein can be exploited to formulate a different approach to treating renal carcinoma. Matrix metalloproteinases (MMPs) are a group of zinc-dependent endopeptidases that carries out the degradation of the extracellular matrix (ECM), and ECM degradation by MMPs enables cancer invasion and metastasis [129]. The tumor necrosis factor α (TNF-α)-converting enzyme (TACE), which is an A disintegrin and metalloproteinase (ADAM), is a multidomain transmembrane protein that functions as proteinases to produce cell surface ligands important for cell growth and proliferation by cleaving their membrane-bound precursors (a phenomenon called the ‘ectodomain shedding’ of ADAM) [130]. Both MMPs and TACE are under the regulation of the tissue inhibitors of metalloproteinases (TIMPs); hence, promoting TIMP can lead to tumor suppression [131]. In a recent study, bioengineered TIMP-1 with enhanced affinities for Membrane type 1-MMP (MT1-MMP) and TACE was fused with the glycosyl-phosphatidyl inositol (GPI) anchor of a cellular prion protein to increase the colocalization of the modified TIMP and its inhibitory targets on the cell surface [132]. The transduction of these modified TIMP fused with the PrPC anchor in renal carcinoma triggered cellular senescence, disrupted MMP-mediated proteolysis of the ECM, and suppressed cell motility and survival in vitro and in vivo [132]. Here, a creative incorporation of PrPC into a therapeutic design led to a novel approach to stop the progression of metastatic renal carcinoma.

3.3. PrPC and Renal Fibrosis

The promising preclinical data for applying novel therapeutic approaches based on PrPC for AKI, CKD, and renal carcinoma, as discussed above, invites the question of whether PrPC can be useful in treating other renal diseases. Does PrPC have a role to play in diabetic kidney disease, renal fibrosis, polycystic kidney disease, glomerulonephritis, and other common renal illnesses? Out of all, the involvement of PrPC seems the most plausible in renal fibrosis, which results from an overdrive of maladaptive renal tissue repair programs [133,134,135], as new evidence supporting the link between PrPC and the regulation of renal fibrosis is emerging.
For example, it is known that TGF-β1 act as the master regulator of renal fibrogenesis through the canonical TG-Fβ/Smad signaling pathways, which induces excessive production of the extracellular matrix (ECM) while suppressing ECM degradation [136]. One of the other members within the TGF-β superfamily, BMP-7, which induces the BMP/Smad signaling pathways, was found to regulate the expression of a major prion protein precursor gene [97]. BMP-7 is heavily expressed in kidney podocytes, distal tubules, and collecting ducts [137], which correspond with the tissues of kidneys with endogenous PrPC expression. The disappearance of antifibrogenic BMP-7 in the early stages of renal disease has been associated with the progression of renal fibrosis [138], and antifibrotic BMP-7 activates smad5 to inhibit smad6, which induces the translocation of TGF-β-activated smad3 to the nucleus [137]. If PrPC turns out to be involved in the antifibrotic BMP-7 pathway, it could be another promising target for antifibrotic therapy to intervene with the profibrotic effects of TGF-β signaling at its downstream effector level. This would be a more realistic approach compared to direct targeting of TGF-β, as the latter is unlikely to lead to a viable therapy due to the broad involvement of TGF-β in many essential cellular processes [97].
In addition, we previously demonstrated that a melatonin treatment can suppress renal fibrosis by upregulating miR-4516 in kidney tissues [139], and this is consistent with the widely reported antifibrotic effects of melatonin [140,141,201,202]. More recently, we showed that the melatonin-mediated upregulation of miR-4516 promotes PrPC expression [68]. If the miR-4516-induced upregulation of PrPC plays a role in the observed antifibrotic effects, this would add to the existing evidence supporting the validity of PrPC as a potential target for treating renal fibrosis.

4. Conclusions

Despite the emerging body of literature supporting the wide-ranging applicability of PrPC functions in renal physiology and many pathologies where the kidney is either at the center of the disease etiology or suffers from secondary exposure to cellular toxins resulting from other organs, a rigorous characterization of PrPC in kidneys has been trailing behind, and therefore, several questions remain. First, the PrPC expression profile in kidneys under normal and pathologic conditions are not fully understood for various kidney tissues. A low volume of research covering the kidney expression of PrPC poses a great challenge for evaluating the accuracy and reproducibility of each literature. The probing endogenous PrPC expression at the transcript and protein levels in different animal models and serum or plasma samples from a human cohort all concluded that PrPC reports statistically significant differential expressions in kidney tissues for renal and prion diseases, yet the direction of changes in the PrPC expressions diverged, as the reported data alternated between overexpression and downregulation, depending on the model and experimental conditions. This strongly suggests that PrPC expression may be highly context-dependent, and the identification of confounding variables behind PrPC regulation would be a necessary prerequisite in harnessing the functions of PrPC for therapeutic purposes.
Another important question remains for the underlying biological mechanisms of the observed physiological functions of PrPC: does PrPC directly regulate all the pathways that seem to be affected by the differential expression of PrPC? Ccould there be a few core pathways that are the direct primary targets of PrPC-mediated regulation, and the rest are secondary effects caused by the activity of the primary targets? Although many signaling pathways are reportedly activated or inhibited by PrPC, the existence of extensive crosstalk networks between the pathways, coupled with the differential expression of suspected binding partners of PrPC in different tissues/cell types, point towards the probability that there will be a difference in the degree of involvement for the primary and secondary downstream effectors of PrPC [7]. For example, in the PrPC-induced activation of glycolysis in cerebral ischemia, crosstalk between the Wnt/β-catenin and PI3K/Akt signaling pathways is the executor of glycolysis activation, but PrPC interaction with the PI3K/Akt pathway is better documented [7,203]. Mapping the full regulatory network for PrPC in a physiological context could help us identify which cellular pathways are better targeted with PrPC-based interventions for specific renal diseases. As the investigation of the PrPC functions is the most advanced in neurological models, testing the cross-applicability of their findings may yield fruitful results.
The translation of a PrPC-based treatment paradigm into clinical use in the aforementioned conditions would be a big challenge, not only because of the insufficient understanding of PrPC in renal pathophysiology but also because of the relatively unclear pathologic mechanisms of the disease themselves. Thus, further studies should have a balanced focus on both identifying the role and regulatory network of PrPC and the underlying etiology of renal pathology. Meanwhile, improving the viability and functionality of the MSCs for cell therapy by targeting PrPC in extracellular vesicles seems to be the most promising strategy with the broadest applicability. Undertaking clinical trials to test the PrPC-based strategies for enhancing cell therapy for CKD would be the important next step. Taken together, increasing the momentum for researching the cell biology of renal PrPC may provide the necessary foundation for discovering innovative pharmacological or cell-based agents that are effective for kidney failures and renal cancers.

Author Contributions

Conceptualization: S.Y. and G.G.; investigation: S.Y., Y.Y. and J.L.; resources: S.Y. and S.L.; writing—original draft preparation: S.Y.; writing—review and editing: S.Y., Y.Y. and J.L.; visualization: S.Y. and G.L.; supervision: G.G. and S.L.; and project administration: S.Y. and G.G. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by a grant from the National Research Foundation funded by the Korean government (2019M3A9H1103495).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Prusiner, S.B. Novel proteinaceous infectious particles cause scrapie. Science 1982, 216, 136–144. [Google Scholar] [CrossRef] [Green Version]
  2. Sarnataro, D.; Pepe, A.; Zurzolo, C. Cell Biology of Prion Protein. Prog. Mol. Biol. Transl. Sci. 2017, 150, 57–82. [Google Scholar] [CrossRef] [PubMed]
  3. Abskharon, R.N.; Giachin, G.; Wohlkonig, A.; Soror, S.H.; Pardon, E.; Legname, G.; Steyaert, J. Probing the N-terminal beta-sheet conversion in the crystal structure of the human prion protein bound to a nanobody. J. Am. Chem. Soc. 2014, 136, 937–944. [Google Scholar] [CrossRef] [PubMed]
  4. Altmeppen, H.C.; Puig, B.; Dohler, F.; Thurm, D.K.; Falker, C.; Krasemann, S.; Glatzel, M. Proteolytic processing of the prion protein in health and disease. Am. J. Neurodegener. Dis. 2012, 1, 15–31. [Google Scholar] [PubMed]
  5. Christen, B.; Damberger, F.F.; Perez, D.R.; Hornemann, S.; Wuthrich, K. Structural plasticity of the cellular prion protein and implications in health and disease. Proc. Natl. Acad. Sci. USA 2013, 110, 8549–8554. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Zanusso, G.; Liu, D.; Ferrari, S.; Hegyi, I.; Yin, X.; Aguzzi, A.; Hornemann, S.; Liemann, S.; Glockshuber, R.; Manson, J.C.; et al. Prion protein expression in different species: Analysis with a panel of new mAbs. Proc. Natl. Acad. Sci. USA 1998, 95, 8812–8816. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Castle, A.R.; Gill, A.C. Physiological Functions of the Cellular Prion Protein. Front. Mol. Biosci. 2017, 4, 19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Colby, D.W.; Prusiner, S.B. Prions. Cold Spring Harb. Perspect. Biol. 2011, 3, a006833. [Google Scholar] [CrossRef]
  9. Spagnolli, G.; Rigoli, M.; Orioli, S.; Sevillano, A.M.; Faccioli, P.; Wille, H.; Biasini, E.; Requena, J.R. Full atomistic model of prion structure and conversion. PLoS Pathog. 2019, 15, e1007864. [Google Scholar] [CrossRef] [Green Version]
  10. McDonald, A.J.; Millhauser, G.L. PrP overdrive: Does inhibition of alpha-cleavage contribute to PrP(C) toxicity and prion disease? Prion 2014, 8, 183–191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  11. Banks, W.A.; Robinson, S.M.; Diaz-Espinoza, R.; Urayama, A.; Soto, C. Transport of prion protein across the blood-brain barrier. Exp. Neurol 2009, 218, 162–167. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Miele, G.; Alejo Blanco, A.R.; Baybutt, H.; Horvat, S.; Manson, J.; Clinton, M. Embryonic activation and developmental expression of the murine prion protein gene. Gene Expr. 2003, 11, 1–12. [Google Scholar] [CrossRef]
  13. Tichopad, A.; Pfaffl, M.W.; Didier, A. Tissue-specific expression pattern of bovine prion gene: Quantification using real-time RT-PCR. Mol. Cell. Probes 2003, 17, 5–10. [Google Scholar] [CrossRef]
  14. Moudjou, M.; Frobert, Y.; Grassi, J.; La Bonnardiere, C. Cellular prion protein status in sheep: Tissue-specific biochemical signatures. J. Gen. Virol 2001, 82, 2017–2024. [Google Scholar] [CrossRef] [PubMed]
  15. Amselgruber, W.M.; Steffl, M.; Didier, A.; Martlbauer, E.; Pfaff, E.; Buttner, M. Prion protein expression in bovine podocytes and extraglomerular mesangial cells. Cell Tissue Res. 2006, 324, 497–505. [Google Scholar] [CrossRef] [PubMed]
  16. Peralta, O.A.; Eyestone, W.H. Quantitative and qualitative analysis of cellular prion protein (PrP(C)) expression in bovine somatic tissues. Prion 2009, 3, 161–170. [Google Scholar] [CrossRef] [Green Version]
  17. Williams, W.M.; Stadtman, E.R.; Moskovitz, J. Ageing and exposure to oxidative stress in vivo differentially affect cellular levels of PrP in mouse cerebral microvessels and brain parenchyma. Neuropathol. Appl. Neurobiol. 2004, 30, 161–168. [Google Scholar] [CrossRef]
  18. Gasperini, L.; Legname, G. Prion protein and aging. Front. Cell Dev. Biol. 2014, 2, 44. [Google Scholar] [CrossRef] [Green Version]
  19. Harris, D.A.; Lele, P.; Snider, W.D. Localization of the mRNA for a chicken prion protein by in situ hybridization. Proc. Natl. Acad. Sci. USA 1993, 90, 4309–4313. [Google Scholar] [CrossRef] [Green Version]
  20. Thumdee, P.; Ponsuksili, S.; Murani, E.; Nganvongpanit, K.; Gehrig, B.; Tesfaye, D.; Gilles, M.; Hoelker, M.; Jennen, D.; Griese, J.; et al. Expression of the prion protein gene (PRNP) and cellular prion protein (PrPc) in cattle and sheep fetuses and maternal tissues during pregnancy. Gene Expr. 2007, 13, 283–297. [Google Scholar] [CrossRef] [Green Version]
  21. Parchi, P.; Castellani, R.; Cortelli, P.; Montagna, P.; Chen, S.G.; Petersen, R.B.; Manetto, V.; Vnencak-Jones, C.L.; McLean, M.J.; Sheller, J.R.; et al. Regional distribution of protease-resistant prion protein in fatal familial insomnia. Ann. Neurol 1995, 38, 21–29. [Google Scholar] [CrossRef] [PubMed]
  22. Uttley, L.; Carroll, C.; Wong, R.; Hilton, D.A.; Stevenson, M. Creutzfeldt-Jakob disease: A systematic review of global incidence, prevalence, infectivity, and incubation. Lancet Infect. Dis. 2020, 20, e2–e10. [Google Scholar] [CrossRef]
  23. Notari, S.; Qing, L.; Pocchiari, M.; Dagdanova, A.; Hatcher, K.; Dogterom, A.; Groisman, J.F.; Lumholtz, I.B.; Puopolo, M.; Lasmezas, C.; et al. Assessing prion infectivity of human urine in sporadic Creutzfeldt-Jakob disease. Emerg. Infect. Dis. 2012, 18, 21–28. [Google Scholar] [CrossRef] [Green Version]
  24. Brandel, J.P.; Knight, R. Variant Creutzfeldt-Jakob disease. Handb. Clin. Neurol. 2018, 153, 191–205. [Google Scholar] [CrossRef] [PubMed]
  25. Otero, A.; Duque Velasquez, C.; Johnson, C.; Herbst, A.; Bolea, R.; Badiola, J.J.; Aiken, J.; McKenzie, D. Prion protein polymorphisms associated with reduced CWD susceptibility limit peripheral PrP(CWD) deposition in orally infected white-tailed deer. BMC Vet. Res. 2019, 15, 50. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Ligios, C.; Cancedda, G.M.; Margalith, I.; Santucciu, C.; Madau, L.; Maestrale, C.; Basagni, M.; Saba, M.; Heikenwalder, M. Intraepithelial and interstitial deposition of pathological prion protein in kidneys of scrapie-affected sheep. PLoS ONE 2007, 2, e859. [Google Scholar] [CrossRef] [PubMed]
  27. Reichl, H.; Balen, A.; Jansen, C.A. Prion transmission in blood and urine: What are the implications for recombinant and urinary-derived gonadotrophins? Hum. Reprod 2002, 17, 2501–2508. [Google Scholar] [CrossRef] [Green Version]
  28. Tateishi, J. Transmission of Creutzfeldt-Jakob disease from human blood and urine into mice. Lancet 1985, 2, 1074. [Google Scholar] [CrossRef]
  29. Gonzalez-Romero, D.; Barria, M.A.; Leon, P.; Morales, R.; Soto, C. Detection of infectious prions in urine. FEBS Lett. 2008, 582, 3161–3166. [Google Scholar] [CrossRef] [Green Version]
  30. Erana, H.; Charco, J.M.; Gonzalez-Miranda, E.; Garcia-Martinez, S.; Lopez-Moreno, R.; Perez-Castro, M.A.; Diaz-Dominguez, C.M.; Garcia-Salvador, A.; Castilla, J. Detection of Pathognomonic Biomarker PrP(Sc) and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases. Biomolecules 2020, 10, 469. [Google Scholar] [CrossRef] [Green Version]
  31. Takatsuki, H.; Fuse, T.; Nakagaki, T.; Mori, T.; Mihara, B.; Takao, M.; Iwasaki, Y.; Yoshida, M.; Murayama, S.; Atarashi, R.; et al. Prion-Seeding Activity Is widely Distributed in Tissues of Sporadic Creutzfeldt-Jakob Disease Patients. EBioMedicine 2016, 12, 150–155. [Google Scholar] [CrossRef] [Green Version]
  32. Luk, C.; Jones, S.; Thomas, C.; Fox, N.C.; Mok, T.H.; Mead, S.; Collinge, J.; Jackson, G.S. Diagnosing Sporadic Creutzfeldt-Jakob Disease by the Detection of Abnormal Prion Protein in Patient Urine. JAMA Neurol. 2016, 73, 1454–1460. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Halliday, M.; Mallucci, G.R. Targeting the unfolded protein response in neurodegeneration: A new approach to therapy. Neuropharmacology 2014, 76 Pt A, 169–174. [Google Scholar] [CrossRef]
  34. Go, G.; Lee, S.H. The Cellular Prion Protein: A Promising Therapeutic Target for Cancer. Int. J. Mol. Sci. 2020, 21, 9208. [Google Scholar] [CrossRef] [PubMed]
  35. Haigh, C.L.; Tumpach, C.; Drew, S.C.; Collins, S.J. The Prion Protein N1 and N2 Cleavage Fragments Bind to Phosphatidylserine and Phosphatidic Acid; Relevance to Stress-Protection Responses. PLoS ONE 2015, 10, e0134680. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Lee, J.H.; Yoon, Y.M.; Han, Y.S.; Jung, S.K.; Lee, S.H. Melatonin protects mesenchymal stem cells from autophagy-mediated death under ischaemic ER-stress conditions by increasing prion protein expression. Cell Prolif. 2019, 52, e12545. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Rachidi, W.; Vilette, D.; Guiraud, P.; Arlotto, M.; Riondel, J.; Laude, H.; Lehmann, S.; Favier, A. Expression of prion protein increases cellular copper binding and antioxidant enzyme activities but not copper delivery. J. Biol. Chem. 2003, 278, 9064–9072. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Zanetti, F.; Carpi, A.; Menabo, R.; Giorgio, M.; Schulz, R.; Valen, G.; Baysa, A.; Massimino, M.L.; Sorgato, M.C.; Bertoli, A.; et al. The cellular prion protein counteracts cardiac oxidative stress. Cardiovasc. Res. 2014, 104, 93–102. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Watt, N.T.; Routledge, M.N.; Wild, C.P.; Hooper, N.M. Cellular prion protein protects against reactive-oxygen-species-induced DNA damage. Free Radic Biol. Med. 2007, 43, 959–967. [Google Scholar] [CrossRef]
  40. Miranda, A.; Pericuesta, E.; Ramirez, M.A.; Gutierrez-Adan, A. Prion protein expression regulates embryonic stem cell pluripotency and differentiation. PLoS ONE 2011, 6, e18422. [Google Scholar] [CrossRef]
  41. Terra-Granado, E.; Berbert, L.R.; de Meis, J.; Nomizo, R.; Martins, V.R.; Savino, W.; Silva-Barbosa, S.D. Is there a role for cellular prion protein in intrathymic T cell differentiation and migration? Neuroimmunomodulation 2007, 14, 213–219. [Google Scholar] [CrossRef] [PubMed]
  42. Graner, E.; Mercadante, A.F.; Zanata, S.M.; Martins, V.R.; Jay, D.G.; Brentani, R.R. Laminin-induced PC-12 cell differentiation is inhibited following laser inactivation of cellular prion protein. FEBS Lett. 2000, 482, 257–260. [Google Scholar] [CrossRef] [Green Version]
  43. Fleisch, V.C.; Leighton, P.L.; Wang, H.; Pillay, L.M.; Ritzel, R.G.; Bhinder, G.; Roy, B.; Tierney, K.B.; Ali, D.W.; Waskiewicz, A.J.; et al. Targeted mutation of the gene encoding prion protein in zebrafish reveals a conserved role in neuron excitability. Neurobiol. Dis. 2013, 55, 11–25. [Google Scholar] [CrossRef] [PubMed]
  44. Ratte, S.; Vreugdenhil, M.; Boult, J.K.; Patel, A.; Asante, E.A.; Collinge, J.; Jefferys, J.G. Threshold for epileptiform activity is elevated in prion knockout mice. Neuroscience 2011, 179, 56–61. [Google Scholar] [CrossRef]
  45. Robinson, S.W.; Nugent, M.L.; Dinsdale, D.; Steinert, J.R. Prion protein facilitates synaptic vesicle release by enhancing release probability. Hum. Mol. Genet. 2014, 23, 4581–4596. [Google Scholar] [CrossRef] [Green Version]
  46. Bremer, J.; Baumann, F.; Tiberi, C.; Wessig, C.; Fischer, H.; Schwarz, P.; Steele, A.D.; Toyka, K.V.; Nave, K.A.; Weis, J.; et al. Axonal prion protein is required for peripheral myelin maintenance. Nat. Neurosci. 2010, 13, 310–318. [Google Scholar] [CrossRef]
  47. Scalabrino, G.; Veber, D.; Tredici, G. Relationships between cobalamin, epidermal growth factor, and normal prions in the myelin maintenance of central nervous system. Int. J. Biochem. Cell Biol. 2014, 55, 232–241. [Google Scholar] [CrossRef]
  48. Radovanovic, I.; Braun, N.; Giger, O.T.; Mertz, K.; Miele, G.; Prinz, M.; Navarro, B.; Aguzzi, A. Truncated prion protein and Doppel are myelinotoxic in the absence of oligodendrocytic PrPC. J. Neurosci. 2005, 25, 4879–4888. [Google Scholar] [CrossRef] [Green Version]
  49. Cagampang, F.R.; Whatley, S.A.; Mitchell, A.L.; Powell, J.F.; Campbell, I.C.; Coen, C.W. Circadian regulation of prion protein messenger RNA in the rat forebrain: A widespread and synchronous rhythm. Neuroscience 1999, 91, 1201–1204. [Google Scholar] [CrossRef]
  50. Tobler, I.; Gaus, S.E.; Deboer, T.; Achermann, P.; Fischer, M.; Rulicke, T.; Moser, M.; Oesch, B.; McBride, P.A.; Manson, J.C. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature 1996, 380, 639–642. [Google Scholar] [CrossRef]
  51. Singh, A.; Mohan, M.L.; Isaac, A.O.; Luo, X.; Petrak, J.; Vyoral, D.; Singh, N. Prion protein modulates cellular iron uptake: A novel function with implications for prion disease pathogenesis. PLoS ONE 2009, 4, e4468. [Google Scholar] [CrossRef]
  52. Singh, A.; Kong, Q.; Luo, X.; Petersen, R.B.; Meyerson, H.; Singh, N. Prion protein (PrP) knock-out mice show altered iron metabolism: A functional role for PrP in iron uptake and transport. PLoS ONE 2009, 4, e6115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Watt, N.T.; Hooper, N.M. The prion protein and neuronal zinc homeostasis. Trends Biochem. Sci. 2003, 28, 406–410. [Google Scholar] [CrossRef]
  54. Isaacs, J.D.; Jackson, G.S.; Altmann, D.M. The role of the cellular prion protein in the immune system. Clin. Exp. Immunol. 2006, 146, 1–8. [Google Scholar] [CrossRef] [PubMed]
  55. Griffiths, H.H.; Whitehouse, I.J.; Hooper, N.M. Regulation of amyloid-beta production by the prion protein. Prion 2012, 6, 217–222. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Mouillet-Richard, S.; Ermonval, M.; Chebassier, C.; Laplanche, J.L.; Lehmann, S.; Launay, J.M.; Kellermann, O. Signal transduction through prion protein. Science 2000, 289, 1925–1928. [Google Scholar] [CrossRef] [Green Version]
  57. Didonna, A. Prion protein and its role in signal transduction. Cell Mol. Biol. Lett. 2013, 18, 209–230. [Google Scholar] [CrossRef] [PubMed]
  58. Mays, C.E.; Kim, C.; Haldiman, T.; van der Merwe, J.; Lau, A.; Yang, J.; Grams, J.; Di Bari, M.A.; Nonno, R.; Telling, G.C.; et al. Prion disease tempo determined by host-dependent substrate reduction. J. Clin. Investig. 2014, 124, 847–858. [Google Scholar] [CrossRef] [Green Version]
  59. Kuwahara, C.; Takeuchi, A.M.; Nishimura, T.; Haraguchi, K.; Kubosaki, A.; Matsumoto, Y.; Saeki, K.; Matsumoto, Y.; Yokoyama, T.; Itohara, S.; et al. Prions prevent neuronal cell-line death. Nature 1999, 400, 225–226. [Google Scholar] [CrossRef]
  60. Diarra-Mehrpour, M.; Arrabal, S.; Jalil, A.; Pinson, X.; Gaudin, C.; Pietu, G.; Pitaval, A.; Ripoche, H.; Eloit, M.; Dormont, D.; et al. Prion protein prevents human breast carcinoma cell line from tumor necrosis factor alpha-induced cell death. Cancer Res. 2004, 64, 719–727. [Google Scholar] [CrossRef] [Green Version]
  61. Bounhar, Y.; Zhang, Y.; Goodyer, C.G.; LeBlanc, A. Prion protein protects human neurons against Bax-mediated apoptosis. J. Biol. Chem. 2001, 276, 39145–39149. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Kim, B.H.; Lee, H.G.; Choi, J.K.; Kim, J.I.; Choi, E.K.; Carp, R.I.; Kim, Y.S. The cellular prion protein (PrPC) prevents apoptotic neuronal cell death and mitochondrial dysfunction induced by serum deprivation. Brain Res. Mol. Brain Res. 2004, 124, 40–50. [Google Scholar] [CrossRef]
  63. McLennan, N.F.; Brennan, P.M.; McNeill, A.; Davies, I.; Fotheringham, A.; Rennison, K.A.; Ritchie, D.; Brannan, F.; Head, M.W.; Ironside, J.W.; et al. Prion protein accumulation and neuroprotection in hypoxic brain damage. Am. J. Pathol. 2004, 165, 227–235. [Google Scholar] [CrossRef] [Green Version]
  64. Shyu, W.C.; Lin, S.Z.; Chiang, M.F.; Ding, D.C.; Li, K.W.; Chen, S.F.; Yang, H.I.; Li, H. Overexpression of PrPC by adenovirus-mediated gene targeting reduces ischemic injury in a stroke rat model. J. Neurosci. 2005, 25, 8967–8977. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Weise, J.; Sandau, R.; Schwarting, S.; Crome, O.; Wrede, A.; Schulz-Schaeffer, W.; Zerr, I.; Bahr, M. Deletion of cellular prion protein results in reduced Akt activation, enhanced postischemic caspase-3 activation, and exacerbation of ischemic brain injury. Stroke 2006, 37, 1296–1300. [Google Scholar] [CrossRef] [Green Version]
  66. Haldar, S.; Tripathi, A.; Qian, J.; Beserra, A.; Suda, S.; McElwee, M.; Turner, J.; Hopfer, U.; Singh, N. Prion protein promotes kidney iron uptake via its ferrireductase activity. J. Biol. Chem. 2015, 290, 5512–5522. [Google Scholar] [CrossRef] [Green Version]
  67. Bignon, Y.; Poindessous, V.; Lazareth, H.; Passet, B.; Vilotte, J.L.; Djouadi, F.; Mouillet-Richard, S.; Pallet, N. The cellular prion protein is a stress protein secreted by renal tubular cells and a urinary marker of kidney injury. Cell Death Dis. 2020, 11, 243. [Google Scholar] [CrossRef]
  68. Yoon, Y.M.; Lee, J.H.; Song, K.H.; Noh, H.; Lee, S.H. Melatonin-stimulated exosomes enhance the regenerative potential of chronic kidney disease-derived mesenchymal stem/stromal cells via cellular prion proteins. J. Pineal. Res. 2020, 68, e12632. [Google Scholar] [CrossRef]
  69. Kobayashi, N.; Gao, S.Y.; Chen, J.; Saito, K.; Miyawaki, K.; Li, C.Y.; Pan, L.; Saito, S.; Terashita, T.; Matsuda, S. Process formation of the renal glomerular podocyte: Is there common molecular machinery for processes of podocytes and neurons? Anat. Sci. Int. 2004, 79, 1–10. [Google Scholar] [CrossRef]
  70. Rastaldi, M.P.; Armelloni, S.; Berra, S.; Calvaresi, N.; Corbelli, A.; Giardino, L.A.; Li, M.; Wang, G.Q.; Fornasieri, A.; Villa, A.; et al. Glomerular podocytes contain neuron-like functional synaptic vesicles. FASEB J. 2006, 20, 976–978. [Google Scholar] [CrossRef]
  71. Sun, Y.; Zhang, H.; Hu, R.; Sun, J.; Mao, X.; Zhao, Z.; Chen, Q.; Zhang, Z. The expression and significance of neuronal iconic proteins in podocytes. PLoS ONE 2014, 9, e93999. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Lopes, M.H.; Hajj, G.N.; Muras, A.G.; Mancini, G.L.; Castro, R.M.; Ribeiro, K.C.; Brentani, R.R.; Linden, R.; Martins, V.R. Interaction of cellular prion and stress-inducible protein 1 promotes neuritogenesis and neuroprotection by distinct signaling pathways. J. Neurosci. 2005, 25, 11330–11339. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Caetano, F.A.; Lopes, M.H.; Hajj, G.N.; Machado, C.F.; Pinto Arantes, C.; Magalhaes, A.C.; Vieira Mde, P.; Americo, T.A.; Massensini, A.R.; Priola, S.A.; et al. Endocytosis of prion protein is required for ERK1/2 signaling induced by stress-inducible protein 1. J. Neurosci. 2008, 28, 6691–6702. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Beraldo, F.H.; Arantes, C.P.; Santos, T.G.; Machado, C.F.; Roffe, M.; Hajj, G.N.; Lee, K.S.; Magalhaes, A.C.; Caetano, F.A.; Mancini, G.L.; et al. Metabotropic glutamate receptors transduce signals for neurite outgrowth after binding of the prion protein to laminin gamma1 chain. FASEB J. 2011, 25, 265–279. [Google Scholar] [CrossRef]
  75. Vassallo, N.; Herms, J.; Behrens, C.; Krebs, B.; Saeki, K.; Onodera, T.; Windl, O.; Kretzschmar, H.A. Activation of phosphatidylinositol 3-kinase by cellular prion protein and its role in cell survival. Biochem. Biophys. Res. Commun. 2005, 332, 75–82. [Google Scholar] [CrossRef] [PubMed]
  76. Schultze, S.M.; Hemmings, B.A.; Niessen, M.; Tschopp, O. PI3K/AKT, MAPK and AMPK signalling: Protein kinases in glucose homeostasis. Expert Rev. Mol. Med. 2012, 14, e1. [Google Scholar] [CrossRef] [Green Version]
  77. Roffe, M.; Beraldo, F.H.; Bester, R.; Nunziante, M.; Bach, C.; Mancini, G.; Gilch, S.; Vorberg, I.; Castilho, B.A.; Martins, V.R.; et al. Prion protein interaction with stress-inducible protein 1 enhances neuronal protein synthesis via mTOR. Proc. Natl. Acad. Sci. USA 2010, 107, 13147–13152. [Google Scholar] [CrossRef] [Green Version]
  78. Kuffer, A.; Lakkaraju, A.K.; Mogha, A.; Petersen, S.C.; Airich, K.; Doucerain, C.; Marpakwar, R.; Bakirci, P.; Senatore, A.; Monnard, A.; et al. The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6. Nature 2016, 536, 464–468. [Google Scholar] [CrossRef]
  79. Krebs, B.; Wiebelitz, A.; Balitzki-Korte, B.; Vassallo, N.; Paluch, S.; Mitteregger, G.; Onodera, T.; Kretzschmar, H.A.; Herms, J. Cellular prion protein modulates the intracellular calcium response to hydrogen peroxide. J. Neurochem. 2007, 100, 358–367. [Google Scholar] [CrossRef]
  80. Chen, R.J.; Chang, W.W.; Lin, Y.C.; Cheng, P.L.; Chen, Y.R. Alzheimer’s amyloid-beta oligomers rescue cellular prion protein induced tau reduction via the Fyn pathway. ACS Chem. Neurosci. 2013, 4, 1287–1296. [Google Scholar] [CrossRef] [Green Version]
  81. Loubet, D.; Dakowski, C.; Pietri, M.; Pradines, E.; Bernard, S.; Callebert, J.; Ardila-Osorio, H.; Mouillet-Richard, S.; Launay, J.M.; Kellermann, O.; et al. Neuritogenesis: The prion protein controls beta1 integrin signaling activity. FASEB J. 2012, 26, 678–690. [Google Scholar] [CrossRef] [PubMed]
  82. Schneider, B.; Pietri, M.; Pradines, E.; Loubet, D.; Launay, J.M.; Kellermann, O.; Mouillet-Richard, S. Understanding the neurospecificity of Prion protein signaling. Front. Biosci. (Landmark Ed.) 2011, 16, 169–186. [Google Scholar] [CrossRef] [PubMed]
  83. Sawe, N.; Steinberg, G.; Zhao, H. Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J. Neurosci. Res. 2008, 86, 1659–1669. [Google Scholar] [CrossRef]
  84. Yang, Y.; Zhang, X.; Cui, H.; Zhang, C.; Zhu, C.; Li, L. Apelin-13 protects the brain against ischemia/reperfusion injury through activating PI3K/Akt and ERK1/2 signaling pathways. Neurosci. Lett 2014, 568, 44–49. [Google Scholar] [CrossRef] [PubMed]
  85. Steele, A.D.; Zhou, Z.; Jackson, W.S.; Zhu, C.; Auluck, P.; Moskowitz, M.A.; Chesselet, M.F.; Lindquist, S. Context dependent neuroprotective properties of prion protein (PrP). Prion 2009, 3, 240–249. [Google Scholar] [CrossRef] [Green Version]
  86. Zhang, B.; Cowden, D.; Zhang, F.; Yuan, J.; Siedlak, S.; Abouelsaad, M.; Zeng, L.; Zhou, X.; O’Toole, J.; Das, A.S.; et al. Prion Protein Protects against Renal Ischemia/Reperfusion Injury. PLoS ONE 2015, 10, e0136923. [Google Scholar] [CrossRef]
  87. Spudich, A.; Frigg, R.; Kilic, E.; Kilic, U.; Oesch, B.; Raeber, A.; Bassetti, C.L.; Hermann, D.M. Aggravation of ischemic brain injury by prion protein deficiency: Role of ERK-1/-2 and STAT-1. Neurobiol. Dis. 2005, 20, 442–449. [Google Scholar] [CrossRef]
  88. Weise, J.; Doeppner, T.R.; Muller, T.; Wrede, A.; Schulz-Schaeffer, W.; Zerr, I.; Witte, O.W.; Bahr, M. Overexpression of cellular prion protein alters postischemic Erk1/2 phosphorylation but not Akt phosphorylation and protects against focal cerebral ischemia. Restor. Neurol. Neurosci. 2008, 26, 57–64. [Google Scholar]
  89. Palmer, B.F. The renal tubule in the progression of chronic renal failure. J. Investig. Med. 1997, 45, 346–361. [Google Scholar]
  90. Thurman, J.M. Triggers of inflammation after renal ischemia/reperfusion. Clin. Immunol. 2007, 123, 7–13. [Google Scholar] [CrossRef] [Green Version]
  91. Dudley, A.T.; Lyons, K.M.; Robertson, E.J. A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev. 1995, 9, 2795–2807. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Simon, M.; Maresh, J.G.; Harris, S.E.; Hernandez, J.D.; Arar, M.; Olson, M.S.; Abboud, H.E. Expression of bone morphogenetic protein-7 mRNA in normal and ischemic adult rat kidney. Am. J. Physiol. 1999, 276, F382–F389. [Google Scholar] [CrossRef] [PubMed]
  93. Bosukonda, D.; Shih, M.S.; Sampath, K.T.; Vukicevic, S. Characterization of receptors for osteogenic protein-1/bone morphogenetic protein-7 (OP-1/BMP-7) in rat kidneys. Kidney Int. 2000, 58, 1902–1911. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Almanzar, M.M.; Frazier, K.S.; Dube, P.H.; Piqueras, A.I.; Jones, W.K.; Charette, M.F.; Paredes, A.L. Osteogenic protein-1 mRNA expression is selectively modulated after acute ischemic renal injury. J. Am. Soc. Nephrol. 1998, 9, 1456–1463. [Google Scholar] [CrossRef]
  95. Vukicevic, S.; Basic, V.; Rogic, D.; Basic, N.; Shih, M.S.; Shepard, A.; Jin, D.; Dattatreyamurty, B.; Jones, W.; Dorai, H.; et al. Osteogenic protein-1 (bone morphogenetic protein-7) reduces severity of injury after ischemic acute renal failure in rat. J. Clin. Investig. 1998, 102, 202–214. [Google Scholar] [CrossRef] [Green Version]
  96. Hruska, K.A.; Guo, G.; Wozniak, M.; Martin, D.; Miller, S.; Liapis, H.; Loveday, K.; Klahr, S.; Sampath, T.K.; Morrissey, J. Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction. Am. J. Physiol. Renal Physiol. 2000, 279, F130–F143. [Google Scholar] [CrossRef]
  97. Gould, S.E.; Day, M.; Jones, S.S.; Dorai, H. BMP-7 regulates chemokine, cytokine, and hemodynamic gene expression in proximal tubule cells. Kidney Int. 2002, 61, 51–60. [Google Scholar] [CrossRef] [Green Version]
  98. Yoon, Y.M.; Lee, J.H.; Yun, S.P.; Han, Y.S.; Yun, C.W.; Lee, H.J.; Noh, H.; Lee, S.J.; Han, H.J.; Lee, S.H. Tauroursodeoxycholic acid reduces ER stress by regulating of Akt-dependent cellular prion protein. Sci. Rep. 2016, 6, 39838. [Google Scholar] [CrossRef] [Green Version]
  99. Yoon, Y.M.; Lee, J.H.; Yun, C.W.; Lee, S.H. Pioglitazone Improves the Function of Human Mesenchymal Stem Cells in Chronic Kidney Disease Patients. Int. J. Mol. Sci. 2019, 20, 2314. [Google Scholar] [CrossRef] [Green Version]
  100. Pease, D.; Scheckel, C.; Schaper, E.; Eckhardt, V.; Emmenegger, M.; Xenarios, I.; Aguzzi, A. Genome-wide identification of microRNAs regulating the human prion protein. Brain Pathol. 2019, 29, 232–244. [Google Scholar] [CrossRef] [Green Version]
  101. Neal, C.S.; Michael, M.Z.; Pimlott, L.K.; Yong, T.Y.; Li, J.Y.; Gleadle, J.M. Circulating microRNA expression is reduced in chronic kidney disease. Nephrol. Dial. Transplant. 2011, 26, 3794–3802. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Rudnicki, M.; Perco, P.; D’haene, B.; Leierer, J.; Heinzel, A.; Muhlberger, I.; Schweibert, N.; Sunzenauer, J.; Regele, H.; Kronbichler, A.; et al. Renal microRNA- and RNA-profiles in progressive chronic kidney disease. Eur. J. Clin. Investig. 2016, 46, 213–226. [Google Scholar] [CrossRef]
  103. Assmann, T.S.; Recamonde-Mendoza, M.; de Souza, B.M.; Bauer, A.C.; Crispim, D. MicroRNAs and diabetic kidney disease: Systematic review and bioinformatic analysis. Mol. Cell. Endocrinol. 2018, 477, 90–102. [Google Scholar] [CrossRef]
  104. Liu, Z.; Wang, Y.; Shu, S.; Cai, J.; Tang, C.; Dong, Z. Non-coding RNAs in kidney injury and repair. Am. J. Physiol. Cell Physiol. 2019, 317, C177–C188. [Google Scholar] [CrossRef]
  105. Mitsios, N.; Saka, M.; Krupinski, J.; Pennucci, R.; Sanfeliu, C.; Miguel Turu, M.; Gaffney, J.; Kumar, P.; Kumar, S.; Sullivan, M.; et al. Cellular prion protein is increased in the plasma and peri-infarcted brain tissue after acute stroke. J. Neurosci. Res. 2007, 85, 602–611. [Google Scholar] [CrossRef] [PubMed]
  106. Senator, A.; Rachidi, W.; Lehmann, S.; Favier, A.; Benboubetra, M. Prion protein protects against DNA damage induced by paraquat in cultured cells. Free Radic Biol. Med. 2004, 37, 1224–1230. [Google Scholar] [CrossRef]
  107. Singh, A.; Haldar, S.; Horback, K.; Tom, C.; Zhou, L.; Meyerson, H.; Singh, N. Prion protein regulates iron transport by functioning as a ferrireductase. J. Alzheimers Dis. 2013, 35, 541–552. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Smith, C.P.; Lee, W.K.; Haley, M.; Poulsen, S.B.; Thevenod, F.; Fenton, R.A. Proximal tubule transferrin uptake is modulated by cellular iron and mediated by apical membrane megalin-cubilin complex and transferrin receptor 1. J. Biol. Chem. 2019, 294, 7025–7036. [Google Scholar] [CrossRef] [Green Version]
  109. Tripathi, A.K.; Haldar, S.; Qian, J.; Beserra, A.; Suda, S.; Singh, A.; Hopfer, U.; Chen, S.G.; Garrick, M.D.; Turner, J.R.; et al. Prion protein functions as a ferrireductase partner for ZIP14 and DMT1. Free Radic Biol. Med. 2015, 84, 322–330. [Google Scholar] [CrossRef] [Green Version]
  110. Singh, N.; Asthana, A.; Baksi, S.; Desai, V.; Haldar, S.; Hari, S.; Tripathi, A.K. The prion-ZIP connection: From cousins to partners in iron uptake. Prion 2015, 9, 420–428. [Google Scholar] [CrossRef] [Green Version]
  111. Silva, B.; Faustino, P. An overview of molecular basis of iron metabolism regulation and the associated pathologies. Biochim. Biophys. Acta 2015, 1852, 1347–1359. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Thevenod, F.; Wolff, N.A. Iron transport in the kidney: Implications for physiology and cadmium nephrotoxicity. Metallomics 2016, 8, 17–42. [Google Scholar] [CrossRef] [PubMed]
  113. Van Raaij, S.E.G.; Rennings, A.J.; Biemond, B.J.; Schols, S.E.M.; Wiegerinck, E.T.G.; Roelofs, H.M.J.; Hoorn, E.J.; Walsh, S.B.; Nijenhuis, T.; Swinkels, D.W.; et al. Iron handling by the human kidney: Glomerular filtration and tubular reabsorption both contribute to urinary iron excretion. Am. J. Physiol. Renal Physiol. 2019, 316, F606–F614. [Google Scholar] [CrossRef] [PubMed]
  114. Ponka, P. Cellular iron metabolism. Kidney Int. 1999, 55 (Suppl. 69), S2–S11. [Google Scholar] [CrossRef] [Green Version]
  115. Martines, A.M.; Masereeuw, R.; Tjalsma, H.; Hoenderop, J.G.; Wetzels, J.F.; Swinkels, D.W. Iron metabolism in the pathogenesis of iron-induced kidney injury. Nat. Rev. Nephrol. 2013, 9, 385–398. [Google Scholar] [CrossRef] [PubMed]
  116. Bahrainwala, J.; Berns, J.S. Diagnosis of Iron-Deficiency Anemia in Chronic Kidney Disease. Semin. Nephrol. 2016, 36, 94–98. [Google Scholar] [CrossRef] [PubMed]
  117. Swaminathan, S. Iron Homeostasis Pathways as Therapeutic Targets in Acute Kidney Injury. Nephron 2018, 140, 156–159. [Google Scholar] [CrossRef] [PubMed]
  118. Van Swelm, R.P.L.; Wetzels, J.F.M.; Swinkels, D.W. The multifaceted role of iron in renal health and disease. Nat. Rev. Nephrol. 2020, 16, 77–98. [Google Scholar] [CrossRef]
  119. Liu, H.; Liu, D.; Liu, Y.; Xia, M.; Li, Y.; Li, M.; Liu, H. Comprehensive analysis of circRNA expression profiles and circRNA-associated competing endogenous RNA networks in IgA nephropathy. PeerJ 2020, 8, e10395. [Google Scholar] [CrossRef]
  120. Doshi, S.M.; Friedman, A.N. Diagnosis and Management of Type 2 Diabetic Kidney Disease. Clin. J. Am. Soc. Nephrol. 2017, 12, 1366–1373. [Google Scholar] [CrossRef]
  121. Chatauret, N.; Badet, L.; Barrou, B.; Hauet, T. Ischemia-reperfusion: From cell biology to acute kidney injury. Prog Urol 2014, 24 (Suppl. 1), S4–S12. [Google Scholar] [CrossRef]
  122. Bindroo, S.; Quintanilla Rodriguez, B.S.; Challa, H.J. Renal Failure; StatPearls: Treasure Island, FL, USA, 2021. [Google Scholar]
  123. Winocour, P.H. Diabetes and chronic kidney disease: An increasingly common multi-morbid disease in need of a paradigm shift in care. Diabet. Med. 2018, 35, 300–305. [Google Scholar] [CrossRef] [PubMed]
  124. Thomas, M.C.; Cooper, M.E.; Zimmet, P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat. Rev. Nephrol. 2016, 12, 73–81. [Google Scholar] [CrossRef] [PubMed]
  125. Yap, Y.H.; Say, Y.H. Resistance against tumour necrosis factor alpha apoptosis by the cellular prion protein is cell-specific for oral, colon and kidney cancer cell lines. Cell Biol. Int. 2012, 36, 273–277. [Google Scholar] [CrossRef] [PubMed]
  126. Von Minckwitz, G.; Huang, C.S.; Mano, M.S.; Loibl, S.; Mamounas, E.P.; Untch, M.; Wolmark, N.; Rastogi, P.; Schneeweiss, A.; Redondo, A.; et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N. Engl. J. Med. 2019, 380, 617–628. [Google Scholar] [CrossRef]
  127. Kusuma, G.D.; Carthew, J.; Lim, R.; Frith, J.E. Effect of the Microenvironment on Mesenchymal Stem Cell Paracrine Signaling: Opportunities to Engineer the Therapeutic Effect. Stem Cells Dev. 2017, 26, 617–631. [Google Scholar] [CrossRef]
  128. Mashima, T.; Lee, J.H.; Kamatari, Y.O.; Hayashi, T.; Nagata, T.; Nishikawa, F.; Nishikawa, S.; Kinoshita, M.; Kuwata, K.; Katahira, M. Development and structural determination of an anti-PrP(C) aptamer that blocks pathological conformational conversion of prion protein. Sci. Rep. 2020, 10, 4934. [Google Scholar] [CrossRef] [Green Version]
  129. Kessenbrock, K.; Plaks, V.; Werb, Z. Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell 2010, 141, 52–67. [Google Scholar] [CrossRef] [Green Version]
  130. Black, R.A. Tumor necrosis factor-alpha converting enzyme. Int. J. Biochem. Cell Biol. 2002, 34, 1–5. [Google Scholar] [CrossRef]
  131. Brew, K.; Nagase, H. The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity. Biochim. Biophys. Acta 2010, 1803, 55–71. [Google Scholar] [CrossRef] [Green Version]
  132. Jiang, B.; Xu, Y.; Zhang, Y.; Lee, M.H. Translocating a High-Affinity Designer TIMP-1 to the Cell Membrane for Total Renal Carcinoma Inhibition: Putting the Prion Protein to Good Use. Mol. Cell. Biol. 2019, 39, e00128-19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Liu, Y. Cellular and molecular mechanisms of renal fibrosis. Nat. Rev. Nephrol. 2011, 7, 684–696. [Google Scholar] [CrossRef]
  134. Yu, S.M.; Bonventre, J.V. Acute kidney injury and maladaptive tubular repair leading to renal fibrosis. Curr. Opin. Nephrol. Hypertens. 2020, 29, 310–318. [Google Scholar] [CrossRef] [PubMed]
  135. Kishi, S.; Brooks, C.R.; Taguchi, K.; Ichimura, T.; Mori, Y.; Akinfolarin, A.; Gupta, N.; Galichon, P.; Elias, B.C.; Suzuki, T.; et al. Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses. J. Clin. Investig. 2019, 129, 4797–4816. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Meng, X.M.; Nikolic-Paterson, D.J.; Lan, H.Y. TGF-beta: The master regulator of fibrosis. Nat. Rev. Nephrol. 2016, 12, 325–338. [Google Scholar] [CrossRef] [PubMed]
  137. Mitu, G.; Hirschberg, R. Bone morphogenetic protein-7 (BMP7) in chronic kidney disease. Front. Biosci. 2008, 13, 4726–4739. [Google Scholar] [CrossRef] [PubMed]
  138. Li, R.X.; Yiu, W.H.; Tang, S.C. Role of bone morphogenetic protein-7 in renal fibrosis. Front. Physiol. 2015, 6, 114. [Google Scholar] [CrossRef] [Green Version]
  139. Yoon, Y.M.; Go, G.; Yun, C.W.; Lim, J.H.; Lee, J.H.; Lee, S.H. Melatonin Suppresses Renal Cortical Fibrosis by Inhibiting Cytoskeleton Reorganization and Mitochondrial Dysfunction through Regulation of miR-4516. Int. J. Mol. Sci. 2020, 21, 5323. [Google Scholar] [CrossRef]
  140. Chen, D.Q.; Cao, G.; Zhao, H.; Chen, L.; Yang, T.; Wang, M.; Vaziri, N.D.; Guo, Y.; Zhao, Y.Y. Combined melatonin and poricoic acid A inhibits renal fibrosis through modulating the interaction of Smad3 and beta-catenin pathway in AKI-to-CKD continuum. Ther. Adv. Chronic Dis. 2019, 10, 2040622319869116. [Google Scholar] [CrossRef] [Green Version]
  141. Fan, Z.; Qi, X.; Yang, W.; Xia, L.; Wu, Y. Melatonin Ameliorates Renal Fibrosis Through the Inhibition of NF-kappaB and TGF-beta1/Smad3 Pathways in db/db Diabetic Mice. Arch. Med. Res. 2020, 51, 524–534. [Google Scholar] [CrossRef]
  142. Watts, J.C.; Bourkas, M.E.C.; Arshad, H. The function of the cellular prion protein in health and disease. Acta Neuropathol. 2018, 135, 159–178. [Google Scholar] [CrossRef] [PubMed]
  143. Ferenbach, D.A.; Bonventre, J.V. Acute kidney injury and chronic kidney disease: From the laboratory to the clinic. Nephrol. Ther. 2016, 12 (Suppl. 1), S41–S48. [Google Scholar] [CrossRef] [Green Version]
  144. Drawz, P.; Rahman, M. Chronic kidney disease. Ann. Intern. Med. 2015, 162, ITC1-16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Haller, H.; Strauer, B.E. [Renal failure]. Internist (Berl.) 2012, 53, 789–790. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Abuelo, J.G. Renal failure caused by chemicals, foods, plants, animal venoms, and misuse of drugs. An overview. Arch. Intern. Med. 1990, 150, 505–510. [Google Scholar] [CrossRef]
  147. Kemmner, S.; Verbeek, M.; Heemann, U. Renal dysfunction following bone marrow transplantation. J. Nephrol. 2017, 30, 201–209. [Google Scholar] [CrossRef]
  148. Shen, Y.; Cai, R.; Sun, J.; Dong, X.; Huang, R.; Tian, S.; Wang, S. Diabetes mellitus as a risk factor for incident chronic kidney disease and end-stage renal disease in women compared with men: A systematic review and meta-analysis. Endocrine 2017, 55, 66–76. [Google Scholar] [CrossRef]
  149. Scolari, F.; Ravani, P. Atheroembolic renal disease. Lancet 2010, 375, 1650–1660. [Google Scholar] [CrossRef] [Green Version]
  150. Bellomo, R.; Kellum, J.A.; Ronco, C. Acute kidney injury. Lancet 2012, 380, 756–766. [Google Scholar] [CrossRef]
  151. Jha, V.; Garcia-Garcia, G.; Iseki, K.; Li, Z.; Naicker, S.; Plattner, B.; Saran, R.; Wang, A.Y.; Yang, C.W. Chronic kidney disease: Global dimension and perspectives. Lancet 2013, 382, 260–272. [Google Scholar] [CrossRef]
  152. Negi, S.; Koreeda, D.; Kobayashi, S.; Yano, T.; Tatsuta, K.; Mima, T.; Shigematsu, T.; Ohya, M. Acute kidney injury: Epidemiology, outcomes, complications, and therapeutic strategies. Semin. Dial. 2018, 31, 519–527. [Google Scholar] [CrossRef] [PubMed]
  153. Stevens, P.E.; Levin, A.; for the Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: Synopsis of the kidney disease: Improving global outcomes 2012 clinical practice guideline. Ann. Intern. Med. 2013, 158, 825–830. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Belayev, L.Y.; Palevsky, P.M. The link between acute kidney injury and chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 2014, 23, 149–154. [Google Scholar] [CrossRef] [PubMed]
  155. Chawla, L.S.; Kimmel, P.L. Acute kidney injury and chronic kidney disease: An integrated clinical syndrome. Kidney Int. 2012, 82, 516–524. [Google Scholar] [CrossRef] [Green Version]
  156. Pannu, N. Bidirectional relationships between acute kidney injury and chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 2013, 22, 351–356. [Google Scholar] [CrossRef]
  157. Malek, M.; Nematbakhsh, M. Renal ischemia/reperfusion injury; from pathophysiology to treatment. J. Renal Inj. Prev. 2015, 4, 20–27. [Google Scholar] [CrossRef]
  158. Bonventre, J.V.; Yang, L. Cellular pathophysiology of ischemic acute kidney injury. J. Clin. Investig. 2011, 121, 4210–4221. [Google Scholar] [CrossRef]
  159. Sharfuddin, A.A.; Molitoris, B.A. Pathophysiology of ischemic acute kidney injury. Nat. Rev. Nephrol. 2011, 7, 189–200. [Google Scholar] [CrossRef]
  160. Liu, J.; Kumar, S.; Dolzhenko, E.; Alvarado, G.F.; Guo, J.; Lu, C.; Chen, Y.; Li, M.; Dessing, M.C.; Parvez, R.K.; et al. Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion. JCI Insight 2017, 2, e94716. [Google Scholar] [CrossRef] [Green Version]
  161. Fan, X.L.; Zhang, Y.; Li, X.; Fu, Q.L. Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell Mol. Life Sci. 2020, 77, 2771–2794. [Google Scholar] [CrossRef] [Green Version]
  162. Morigi, M.; Rota, C.; Remuzzi, G. Mesenchymal Stem Cells in Kidney Repair. Methods Mol. Biol. 2016, 1416, 89–107. [Google Scholar] [CrossRef] [PubMed]
  163. Papazova, D.A.; Oosterhuis, N.R.; Gremmels, H.; van Koppen, A.; Joles, J.A.; Verhaar, M.C. Cell-based therapies for experimental chronic kidney disease: A systematic review and meta-analysis. Dis. Model. Mech. 2015, 8, 281–293. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Villanueva, S.; Gonzalez, F.; Lorca, E.; Tapia, A.; Lopez, V.G.; Strodthoff, R.; Fajre, F.; Carreno, J.E.; Valjalo, R.; Vergara, C.; et al. Adipose tissue-derived mesenchymal stromal cells for treating chronic kidney disease: A pilot study assessing safety and clinical feasibility. Kidney Res. Clin. Pract 2019, 38, 176–185. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Chung, B.H. Use of mesenchymal stem cells for chronic kidney disease. Kidney Res. Clin. Pract. 2019, 38, 131–134. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Yun, C.W.; Lee, S.H. Potential and Therapeutic Efficacy of Cell-Based Therapy Using Mesenchymal Stem Cells for Acute/Chronic Kidney Disease. Int. J. Mol. Sci. 2019, 20, 1619. [Google Scholar] [CrossRef] [Green Version]
  167. Urt-Filho, A.; Oliveira, R.J.; Hermeto, L.C.; Pesarini, J.R.; David, N.; Cantero Wde, B.; Falcao, G.; Marks, G.; Antoniolli-Silva, A.C. Mesenchymal stem cell therapy promotes the improvement and recovery of renal function in a preclinical model. Genet. Mol. Biol. 2016, 39, 290–299. [Google Scholar] [CrossRef]
  168. Huang, Y.C.; Leung, V.Y.; Lu, W.W.; Luk, K.D. The effects of microenvironment in mesenchymal stem cell-based regeneration of intervertebral disc. Spine J. 2013, 13, 352–362. [Google Scholar] [CrossRef]
  169. Teng, X.; Chen, L.; Chen, W.; Yang, J.; Yang, Z.; Shen, Z. Mesenchymal Stem Cell-Derived Exosomes Improve the Microenvironment of Infarcted Myocardium Contributing to Angiogenesis and Anti-Inflammation. Cell Physiol. Biochem. 2015, 37, 2415–2424. [Google Scholar] [CrossRef]
  170. Han, Y.S.; Lee, J.H.; Yoon, Y.M.; Yun, C.W.; Noh, H.; Lee, S.H. Hypoxia-induced expression of cellular prion protein improves the therapeutic potential of mesenchymal stem cells. Cell Death Dis. 2016, 7, e2395. [Google Scholar] [CrossRef]
  171. Lee, J.H.; Yoon, Y.M.; Lee, S.H. TUDCA-Treated Mesenchymal Stem Cells Protect against ER Stress in the Hippocampus of a Murine Chronic Kidney Disease Model. Int. J. Mol. Sci. 2019, 20, 613. [Google Scholar] [CrossRef] [Green Version]
  172. Yun, S.P.; Yoon, Y.M.; Lee, J.H.; Kook, M.; Han, Y.S.; Jung, S.K.; Lee, S.H. Tauroursodeoxycholic Acid Protects against the Effects of P-Cresol-Induced Reactive Oxygen Species via the Expression of Cellular Prion Protein. Int. J. Mol. Sci. 2018, 19, 352. [Google Scholar] [CrossRef] [Green Version]
  173. Fernandez, A.; Ordonez, R.; Reiter, R.J.; Gonzalez-Gallego, J.; Mauriz, J.L. Melatonin and endoplasmic reticulum stress: Relation to autophagy and apoptosis. J. Pineal. Res. 2015, 59, 292–307. [Google Scholar] [CrossRef] [PubMed]
  174. Mias, C.; Trouche, E.; Seguelas, M.H.; Calcagno, F.; Dignat-George, F.; Sabatier, F.; Piercecchi-Marti, M.D.; Daniel, L.; Bianchi, P.; Calise, D.; et al. Ex vivo pretreatment with melatonin improves survival, proangiogenic/mitogenic activity, and efficiency of mesenchymal stem cells injected into ischemic kidney. Stem Cells 2008, 26, 1749–1757. [Google Scholar] [CrossRef] [PubMed]
  175. Han, Y.S.; Kim, S.M.; Lee, J.H.; Jung, S.K.; Noh, H.; Lee, S.H. Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrPC-dependent enhancement of the mitochondrial function. J. Pineal Res. 2019, 66, e12535. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  176. Camussi, G.; Deregibus, M.C.; Bruno, S.; Cantaluppi, V.; Biancone, L. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int. 2010, 78, 838–848. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  177. Bruno, S.; Porta, S.; Bussolati, B. Extracellular vesicles in renal tissue damage and regeneration. Eur. J. Pharmacol. 2016, 790, 83–91. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  178. Borges, F.T.; Reis, L.A.; Schor, N. Extracellular vesicles: Structure, function, and potential clinical uses in renal diseases. Braz. J. Med. Biol. Res. 2013, 46, 824–830. [Google Scholar] [CrossRef] [Green Version]
  179. Zhang, W.; Zhou, X.; Zhang, H.; Yao, Q.; Liu, Y.; Dong, Z. Extracellular vesicles in diagnosis and therapy of kidney diseases. Am. J. Physiol. Renal Physiol. 2016, 311, F844–F851. [Google Scholar] [CrossRef] [Green Version]
  180. Jing, H.; Tang, S.; Lin, S.; Liao, M.; Chen, H.; Zhou, J. The role of extracellular vesicles in renal fibrosis. Cell Death Dis. 2019, 10, 367. [Google Scholar] [CrossRef] [Green Version]
  181. Lv, L.L.; Wu, W.J.; Feng, Y.; Li, Z.L.; Tang, T.T.; Liu, B.C. Therapeutic application of extracellular vesicles in kidney disease: Promises and challenges. J. Cell Mol. Med. 2018, 22, 728–737. [Google Scholar] [CrossRef]
  182. Shen, B.; Liu, J.; Zhang, F.; Wang, Y.; Qin, Y.; Zhou, Z.; Qiu, J.; Fan, Y. CCR2 Positive Exosome Released by Mesenchymal Stem Cells Suppresses Macrophage Functions and Alleviates Ischemia/Reperfusion-Induced Renal Injury. Stem Cells Int. 2016, 2016, 1240301. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  183. Cai, J.; Wu, J.; Wang, J.; Li, Y.; Hu, X.; Luo, S.; Xiang, D. Extracellular vesicles derived from different sources of mesenchymal stem cells: Therapeutic effects and translational potential. Cell Biosci. 2020, 10, 69. [Google Scholar] [CrossRef] [PubMed]
  184. Cantaluppi, V.; Gatti, S.; Medica, D.; Figliolini, F.; Bruno, S.; Deregibus, M.C.; Sordi, A.; Biancone, L.; Tetta, C.; Camussi, G. Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells. Kidney Int. 2012, 82, 412–427. [Google Scholar] [CrossRef] [Green Version]
  185. Lv, L.L.; Feng, Y.; Wu, M.; Wang, B.; Li, Z.L.; Zhong, X.; Wu, W.J.; Chen, J.; Ni, H.F.; Tang, T.T.; et al. Exosomal miRNA-19b-3p of tubular epithelial cells promotes M1 macrophage activation in kidney injury. Cell Death Differ. 2020, 27, 210–226. [Google Scholar] [CrossRef] [PubMed]
  186. Bruno, S.; Grange, C.; Collino, F.; Deregibus, M.C.; Cantaluppi, V.; Biancone, L.; Tetta, C.; Camussi, G. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS ONE 2012, 7, e33115. [Google Scholar] [CrossRef] [PubMed]
  187. Eirin, A.; Zhu, X.Y.; Puranik, A.S.; Tang, H.; McGurren, K.A.; van Wijnen, A.J.; Lerman, A.; Lerman, L.O. Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation. Kidney Int. 2017, 92, 114–124. [Google Scholar] [CrossRef] [PubMed]
  188. Collino, F.; Bruno, S.; Incarnato, D.; Dettori, D.; Neri, F.; Provero, P.; Pomatto, M.; Oliviero, S.; Tetta, C.; Quesenberry, P.J.; et al. AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs. J. Am. Soc. Nephrol. 2015, 26, 2349–2360. [Google Scholar] [CrossRef]
  189. Vinas, J.L.; Burger, D.; Zimpelmann, J.; Haneef, R.; Knoll, W.; Campbell, P.; Gutsol, A.; Carter, A.; Allan, D.S.; Burns, K.D. Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury. Kidney Int. 2016, 90, 1238–1250. [Google Scholar] [CrossRef] [Green Version]
  190. Yoon, Y.M.; Han, Y.S.; Yun, C.W.; Lee, J.H.; Kim, R.; Lee, S.H. Pioglitazone Protects Mesenchymal Stem Cells against P-Cresol-Induced Mitochondrial Dysfunction via Up-Regulation of PINK-1. Int. J. Mol. Sci. 2018, 19, 2898. [Google Scholar] [CrossRef] [Green Version]
  191. Starke, R.; Mackie, I.; Drummond, O.; MacGregor, I.; Harrison, P.; Machin, S. Prion protein in patients with renal failure. Transfus. Med. 2006, 16, 165–168. [Google Scholar] [CrossRef]
  192. Van der Vorm, L.N.; Visser, R.; Huskens, D.; Veninga, A.; Adams, D.L.; Remijn, J.A.; Hemker, H.C.; Rensma, P.L.; van Horssen, R.; de Laat, B. Circulating active von Willebrand factor levels are increased in chronic kidney disease and end-stage renal disease. Clin. Kidney J. 2020, 13, 72–74. [Google Scholar] [CrossRef] [PubMed]
  193. McEwan, J.F.; Windsor, M.L.; Cullis-Hill, S.D. Antibodies to prion protein inhibit human colon cancer cell growth. Tumour Biol. 2009, 30, 141–147. [Google Scholar] [CrossRef] [PubMed]
  194. Hosoya, H.; Sidana, S. Antibody-Based Treatment Approaches in Multiple Myeloma. Curr. Hematol. Malig Rep. 2021. [Google Scholar] [CrossRef] [PubMed]
  195. Bodyak, N.D.; Mosher, R.; Yurkovetskiy, A.V.; Yin, M.; Bu, C.; Conlon, P.R.; Demady, D.R.; DeVit, M.J.; Gumerov, D.R.; Gurijala, V.R.; et al. The Dolaflexin-based antibody-drug conjugate XMT-1536 targets the solid tumor lineage antigen SLC34A2/NaPi2b. Mol. Cancer Ther. 2021. [Google Scholar] [CrossRef]
  196. Sutherland, M.S.; Sanderson, R.J.; Gordon, K.A.; Andreyka, J.; Cerveny, C.G.; Yu, C.; Lewis, T.S.; Meyer, D.L.; Zabinski, R.F.; Doronina, S.O.; et al. Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J. Biol. Chem. 2006, 281, 10540–10547. [Google Scholar] [CrossRef] [Green Version]
  197. Verma, S.; Miles, D.; Gianni, L.; Krop, I.E.; Welslau, M.; Baselga, J.; Pegram, M.; Oh, D.Y.; Dieras, V.; Guardino, E.; et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 2012, 367, 1783–1791. [Google Scholar] [CrossRef] [Green Version]
  198. Xuan, W.; Peng, Y.; Deng, Z.; Peng, T.; Kuai, H.; Li, Y.; He, J.; Jin, C.; Liu, Y.; Wang, R.; et al. A basic insight into aptamer-drug conjugates (ApDCs). Biomaterials 2018, 182, 216–226. [Google Scholar] [CrossRef]
  199. Zhu, G.; Niu, G.; Chen, X. Aptamer-Drug Conjugates. Bioconjug. Chem. 2015, 26, 2186–2197. [Google Scholar] [CrossRef] [Green Version]
  200. Chen, K.; Liu, B.; Yu, B.; Zhong, W.; Lu, Y.; Zhang, J.; Liao, J.; Liu, J.; Pu, Y.; Qiu, L.; et al. Advances in the development of aptamer drug conjugates for targeted drug delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2017, 9, e1438. [Google Scholar] [CrossRef] [Green Version]
  201. Li, N.; Wang, Z.; Gao, F.; Lei, Y.; Li, Z. Melatonin ameliorates renal fibroblast-myofibroblast transdifferentiation and renal fibrosis through miR-21-5p regulation. J. Cell Mol. Med. 2020, 24, 5615–5628. [Google Scholar] [CrossRef] [Green Version]
  202. Li, J.; Li, N.; Yan, S.; Lu, Y.; Miao, X.; Gu, Z.; Shao, Y. Melatonin attenuates renal fibrosis in diabetic mice by activating the AMPK/PGC1alpha signaling pathway and rescuing mitochondrial function. Mol. Med. Rep. 2019, 19, 1318–1330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  203. Ramljak, S.; Herlyn, H.; Zerr, I. Cellular Prion Protein (PrPc) and Hypoxia: True to Each Other in Good Times and in Bad, in Sickness, and in Health. Front. Cell. Neurosci. 2016, 10, 292. [Google Scholar] [CrossRef] [PubMed] [Green Version]
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Figure 1. Schematics for the general PrPC protein structure and expression profile of PrPC in kidney tissues. (A) A cellular prion protein has multiple distinctive domains. One side of the protein has a helical structure with a GPI anchor, while the other side is an intrinsically disordered polypeptide chain. An octapeptide domain binds to divalent metal ions. (B) Ribbon diagram of the human cellular prion protein (PBD 5yj5) is shown on the left. Pathogenic misfolding of a cellular prion protein can lead to an alternate structure with a high beta sheet content. This is shown on the right with the visualization of PrPSc based on the 4RβS architecture, as proposed by Spagnolli et al., which is one of the more accepted provisionary models for the currently ill-defined PrPSc structure. (C) Endogenous expressions of a cellular prion protein were found in nephron and glomerulus structures. (D) Accumulation of an abnormal prion protein in kidney tissues is observed in various prion disease, where the kidney functions are negatively affected. Prion proteins are taken up by a kidney for filtration and excreted into the urine.
Figure 1. Schematics for the general PrPC protein structure and expression profile of PrPC in kidney tissues. (A) A cellular prion protein has multiple distinctive domains. One side of the protein has a helical structure with a GPI anchor, while the other side is an intrinsically disordered polypeptide chain. An octapeptide domain binds to divalent metal ions. (B) Ribbon diagram of the human cellular prion protein (PBD 5yj5) is shown on the left. Pathogenic misfolding of a cellular prion protein can lead to an alternate structure with a high beta sheet content. This is shown on the right with the visualization of PrPSc based on the 4RβS architecture, as proposed by Spagnolli et al., which is one of the more accepted provisionary models for the currently ill-defined PrPSc structure. (C) Endogenous expressions of a cellular prion protein were found in nephron and glomerulus structures. (D) Accumulation of an abnormal prion protein in kidney tissues is observed in various prion disease, where the kidney functions are negatively affected. Prion proteins are taken up by a kidney for filtration and excreted into the urine.
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Figure 2. Endogenous PrPC in the kidneys plays a role in cellular signaling processes to influence renal physiology. (A) PrPC mediates a variety of downstream signaling pathways via interactions with appropriate binding partners in kidney tissues. There are numerous PrPC-signaling pathways that are characterized in neuronal cells, and some of these have been cross-validated in the kidney, while others have not. The signaling proteins and interaction mechanisms that merit further validation in renal models are shown in grayscale or dotted lines. (B) PrPC has been associated with some protective functions against ischemic injury through affecting the ERK1/2 transduction pathway and heme oxygenase-1 (HO-1). (C) PrPC exhibits ferrireductase activity to promote the uptake of transferrin- (Tf) and non-Tf-bound iron (NTBI) by the kidneys. Fe3+ ions are bound to transferrin, which can enter proximal tubular cells. PrPC ferrireductase activity produces Fe2+, which can be released into the cytoplasm through DMT1 and ZIP14.
Figure 2. Endogenous PrPC in the kidneys plays a role in cellular signaling processes to influence renal physiology. (A) PrPC mediates a variety of downstream signaling pathways via interactions with appropriate binding partners in kidney tissues. There are numerous PrPC-signaling pathways that are characterized in neuronal cells, and some of these have been cross-validated in the kidney, while others have not. The signaling proteins and interaction mechanisms that merit further validation in renal models are shown in grayscale or dotted lines. (B) PrPC has been associated with some protective functions against ischemic injury through affecting the ERK1/2 transduction pathway and heme oxygenase-1 (HO-1). (C) PrPC exhibits ferrireductase activity to promote the uptake of transferrin- (Tf) and non-Tf-bound iron (NTBI) by the kidneys. Fe3+ ions are bound to transferrin, which can enter proximal tubular cells. PrPC ferrireductase activity produces Fe2+, which can be released into the cytoplasm through DMT1 and ZIP14.
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Table
Table 1. Applications of the PrPc functions in designing therapeutic strategies for renal diseases.
Table 1. Applications of the PrPc functions in designing therapeutic strategies for renal diseases.
Kidney DiseasePotential PrPc-Based Therapeutic StrategyProposed Mechanism for the Roles/Effects of PrPcValidated in Renal CellsRelated References
AKI/CKDExpressing PrPc in renal tissues to ameliorate IRI renal damage via gene delivery with the adenovirus vectorPrPc suppresses ERK1/2-dependent tissue damage via apoptosis and mitochondrial regulationYes[35,120,121]
Suppressing PrPc in the kidney to treat the dysregulation of iron homeostasisPrPc ferrireductase activity promotes DMT1 and ZIP14-mediated iron uptake in kidney tissuesNo[23,119,122]
Upregulating PrPc in MSC with melatonin, TUDCA (bile acid), or pioglitazone treatment to improve MSC or EV-based cell therapiesPrPc protects MSCs against the adverse microenvironment in damaged kidneys, enhancing the efficacy of the treatmentYes[24,123,124,125,126]
Renal
Fibrosis		Targeting PrPc downstream of BMP-7 to stop the progression of TGF-β-induced renal fibrosisPrPc precursor gene is regulated by BMP-7, which disappears in fibrosis. Interventions at the PrPc level could help ameliorate the fibrotic effects No[127]
Renal
Carcinoma		Cotreatment of the PrPc antibody and chemotherapeutic agentsReduction of PrPc-related drug resistance and metastasis leads to a better outcomeNo[38,128,129]
Using a PrPc aptamer-conjugated drug delivery system or PrPc antibody–drug conjugates for cancer treatmentTargeting differentially expressed PrPc in cancer cells achieves targeted drug deliveryNo[38,130,131,132,133,134,135,136,137,138]
Fusion of TIMPs with the GPI anchor domain for cell surface expressionIncreased colocalization of PrPc-fused TIMP with its inhibitory target (MMP) increases the anticancer effectNo[139,140,141]
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Yoon, S.; Go, G.; Yoon, Y.; Lim, J.; Lee, G.; Lee, S. Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases. Biomolecules 2021, 11, 784. https://doi.org/10.3390/biom11060784

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Yoon S, Go G, Yoon Y, Lim J, Lee G, Lee S. Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases. Biomolecules. 2021; 11(6):784. https://doi.org/10.3390/biom11060784

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Yoon, Sungtae, Gyeongyun Go, Yeomin Yoon, Jiho Lim, Gaeun Lee, and Sanghun Lee. 2021. "Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases" Biomolecules 11, no. 6: 784. https://doi.org/10.3390/biom11060784

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