Akebia Saponin D ameliorated kidney injury and exerted anti-inflammatory and anti-apoptotic effects in diabetic nephropathy by activation of NRF2/HO-1 and inhibition of NF-KB pathway
Introduction
Type 2 diabetes mellitus (T2DM) is a common chronic metabolic disease featured by hyperglycemia, insulin resistance and relative insulin deficiency [1]. In recent years, T2DM has an increasing incidence worldwide with the improvement of people's living standard [2]. As a common microvascular complication of T2DM, diabetic nephropathy (DN) is one of the major causes of renal failure and end-stage renal disease (ESRD) [3]. Current treatment approaches of DN include strict control of blood glucose, reduction of blood pressure and albuminuria by renal-angiotensin-aldosterone system blockers [4], [5]. However, these methods can only improve symptom, and specific therapeutics of DN are still not available.
The pathogenesis of DN is very complex, and the exact mechanism is still unclear [6]. So far, a series of studies have contributed to the research progress of DN pathogenesis [7]. Abnormal glucose metabolism, inflammation, oxidative stress and some other pathological factors have been confirmed to participate in the occurrence and progress of DN [8]. Thus, searching for drugs with anti-inflammatory and anti-oxidation function may have higher values on curing DN.
Nuclear factor kappa-B (NF-κB) is a nuclear protein found in B lymphocyte precursor cells [9]. It has been widely recognized that NF-κB is an important transcription factor in the inflammatory response and mediated in the expression of inflammatory cytokines [10]. Nuclear factor erythroid-2-related factor 2 (Nrf2) is the central regulator of oxidative stress reaction [11]. Oncebeing activated, it transfers to the nucleus and initiates the downstream pathway, thus exerting an anti-oxidative stress function [12]. Heme oxygenase 1 (HO-1) is by far the most classical approach by which Nrf2 works [13]. Researches have proved that modulation of NF-κB and Nrf2/HO-1 pathways can affect DN by adjusting inflammatory status and oxidative stress [14]. Therefore, targeting NF-κB and Nrf2/HO-1 pathways might be a potential therapy against DN.
Numerous studies have shown that a variety of natural products can treat DN and have broad development prospects [15]. Asperosaponin VI, also known as Akebia saponin D (ASD), is the main active ingredient of Dipsaci Radix [16]. Studies have demonstrated that ASD has a wide range of pharmacological effects, such as neuroprotection, myocardial protection, prevention of osteoporosis, anti-apoptotic and hepatoprotective effects [17]. A research had indicated that ASD suppresses TNF-α, IL-1β and COX-2 in brain by activating NF-κB pathway [18]. Besides, aqueous extract of Dipsaci Radix exerts anti-inflammatory and anti-oxidative activities through inhibiting NF-κB and activating Nrf2/HO-1 pathway in macrophages [19]. However, the effects of ASD on the pathogenesis of DN have not yet been elucidated. Therefore, the animal model established by STZ injection to C57BL/6 mice and the cell model conducted by HG induction in HK-2 cells in our current study are adopted to study the protective of ASD and to further investigate the effects and underling mechanism on oxidative stress, inflammation and renal injury in DN.
Section snippets
Experimental animals
A total of 40 male C57BL/6 mice (7-week-old) were obtained from the Animal Center of Nanjing Medical University. Mice were housed in a controlled environmental conditions at 22 ± 2.0 °C and 50–60% humidity with a 12 h light/dark cycle and allowed free access to food and water. All animal procedures were approved by the Ethics Committee of Dongying people's Hospital. The experimental procedure followed the Guidelines for the Care and Use of Laboratory Animals and the “3R” principle.
Induction of diabetes mellitus model
Following
Effects of ASD on blood glucose and insulin levels in diabetic nephropathy mice
Male C57BL/6 mice were injected intraperitoneally with freshly prepared streptozotocin (STZ, Sigma) at a dose of 60 mg/kg for 5 days continuously. As shown in Fig. 1A, the blood glucose levels of diabetic mice were significantly increased compared with those of normal mice while those of mice receiving ASD treatment obviously reduced. As exhibited in Fig. 1B, the insulin levels were distinctly decreased compared with those of normal mice, whereas, ASD-treated mice presented obviously increased
Discussion
Nowadays, the sharply increased diabetes incidence has become one of the major causes endangering human health [1]. DN, characterized by glomerulosclerosis, tubulointerstitial fibrosis and renal vascular lesions, is one of the main causes of ESRD and death in diabetic patients [3]. There are no specific therapeutics for DN [20]. In diabetes, the renal tubules are affected by metabolic disorders, inflammation, proteinuria, hemodynamic changes and so on, with the consequence of oxidative stress,
Conclusion
The molecular mechanism of ADS against DN are researched aiming at exploiting novel hypoglycemic drug for DN treatment. In conclusion, we present evidence that ADS ameliorates hyperglycemia and DN through the upregulation Nrf2/HO-1 pathway and downregulation NF-κB signaling. Our findings may provide a new insight into the possibility of ADS being a therapeutic drug in DN.
CRediT authorship contribution statement
Congcong Lu: Conceptualization, Validation, Methodology, Investigation, Data curation, Formal analysis, Writing - original draft, Writing - review & editing. Guoxia Fan: Conceptualization, Validation, Methodology, Investigation, Data curation, Formal analysis, Writing - original draft, Writing - review & editing. Dianyun Wang: Conceptualization, Validation, Methodology, Formal analysis, Writing - review & editing.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The analyzed data sets generated during the present study are available from the corresponding author on reasonable request.
References (24)
- et al.
Update of pathophysiology and management of diabetic kidney disease
J. Formos. Med. Assoc.
(2018) - et al.
SGLT2 inhibitors to prevent diabetic kidney disease
Lancet Diabetes Endocrinol..
(2020) - et al.
Adenosine monophosphate-activated protein kinase in diabetic nephropathy
Kidney Res. Clin. Pract.
(2016) - et al.
Chlorogenic acid prevents diabetic nephropathy by inhibiting oxidative stress and inflammation through modulation of the Nrf2/HO-1 and NF-ĸB pathways
Int. Immunopharmacol.
(2018) - et al.
Protective effect of vanillin on diabetic nephropathy by decreasing advanced glycation end products in rats
Life Sci.
(2019) - et al.
Akebia saponin D attenuates ibotenic acid-induced cognitive deficits and pro-apoptotic response in rats: involvement of MAPK signal pathway
Pharmacol. Biochem. Behav.
(2012) - et al.
Akebia Saponin D attenuates amyloid β-induced cognitive deficits and inflammatory response in rats: involvement of Akt/NF-κB pathway
Behav. Brain Res.
(2012) - et al.
Aqueous extract of Dipsacus asperoides suppresses lipopolysaccharide-stimulated inflammatory responses by inhibiting the ERK1/2 signaling pathway in RAW 264.7 macrophages
J. Ethnopharmacol.
(2019) - et al.
Association of Pro12Ala Polymorphism of Peroxisome Proliferator-Activated Receptor gamma 2 (PPARγ2) Gene with Type 2 Diabetes Mellitus in Ethnic Kashmiri Population
Biochem. Genet.
(2017) - et al.
Type 2 diabetes mellitus unawareness, prevalence, trends and risk factors: National Health and Nutrition Examination Survey (NHANES) 1999–2010
J. Int. Med. Res.
(2017)
Verapamil Attenuated Prediabetic Neuropathy in High-Fat Diet-Fed Mice through Inhibiting TXNIP-Mediated Apoptosis and Inflammation
Oxid. Med. Cell Longev.
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2022, Journal of Functional FoodsCitation Excerpt :Among which, oxidative stress induced by hyperglycemia is thought to be the initiating factor of DN (Calle & Hotter, 2020; Cheng et al., 2016). Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that regulates oxidative stress reactions and plays a pivotal role in defending DN (Lu, Fan, & Wang, 2020). The activation of Nrf2 can subsequently up-regulate the expressions of antioxidant factors such as Heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase (NQO1), and therefore to alleviate oxidative stress injury (Ke et al., 2013).
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Contributed equally.