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Therapeutic potential of Nrf-2 pathway in the treatment of diabetic neuropathy and nephropathy

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Abstract

Type 2 diabetes (T2D) is one of the most widely spread metabolic disordersand is also referred as a ‘lifestyle’ disorder. According toa study conducted by IDB, the number of individuals affected with diabetes is expected to increase from 463 to 700 million by the end of year 2045. Thus, there is a great need to developed targeted therapies that can maintain homeostasis of glucose levels and improving insulin sensitivity which can overcome hurdles associated with conventional medicine. Detailed analysis was conducted by analyzing various research and review papers which were searched using MEDLINE and EMBASE using various keywords. This search retrieved the most appropriate content on these molecules targeting Nrf-2 functions and Nrf-2 pathway associated with diabetic neuropathy and nephropathy. In this review article, we have highlighted the role of Nrf-2 in diabetic associated complications of neuropathy and nephropathy. Since hyperglycemia is associated with oxidative stress and inflammation, regulating Nrf-2 activity through various synthetic and natural activators whichmay provide therapeutic benefits for the treatment and mitigation of diabetic neuropathy and nephropathy as well. Based on the available literature on Nrf-2 activity and despite some controversies in the association of Nrf-2 activity and its therapeutic usage, it can be concluded that regulation of this pathway is a trigger in the development of diabetes-associated complications. Thus, targeting this pathway with various activators may emerge as a novel therapy in the treatment of diabetes and diabetes-associated complications.

Graphic abstract

Nrf-2 activation leading to regulation of various downstream pathways responsible for managament of Diabetic neuropathy and nephropathy

Legend: Activities regulated by the activation of Nrf-2 pathway by Natural and Synthetic activators. Various downstream signalling pathway are involved in increase (+) and decrease (−) in levels of Nrf-2 levels. Subsequently controlling various mechanism involved in the pathogenies of Diabetic neuropathy and nephropathy

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Abbreviations

AGE:

Advanced glycation end products

AIDS:

Acquired immunodeficiency syndrome

AKT:

Progressive ankylosis protein

ARE:

Antioxidant response element

ARE:

Anti-oxidant response element

ATF:

Activating transcription factor

bZIP:

Basic leucine zipper

CAT:

Catalase

CBP:

CREB-binding protein

CNC-bZip:

Basic region leucine zipper factor family’

COPD:

Chronic obstructive pulmonary disease

COX-2:

Cyclooxygenase-2

CREB:

CAMP response element binding protein

DMF:

Dimethyl fumarate

DN:

Diabetic nephropathy

DPP-4:

Dipeptidyl peptidase-4

FDA:

Food and drug administration

G-6-PD:

Glucose-6-phosphate dehydrogenase

GCL:

Glutamate cysteine ligase

GCLC:

Glutamate-cysteine ligase catalytic subunit

GCLM:

Glutamate-cysteine ligase catalytic subunit

GLP-1:

Glucagon-like peptide-1

GPx:

Glutathione peroxidase

GSH:

Glutathione

GSK-3:

Glycogen synthase kinase 3

GSK-3β:

Glycogen synthase kinase-3beta

GST:

Glutathione S-transferase

HMOX1:

Heme oxygenase decycling-1

O-1:

Heme oxygenase-1

Hrd1- 3:

Hydroxy-3-methylglutaryl reductase degradation 1

IDF:

International diabetes federation

IRE-1:

Inositol requiring protein

JNK:

C-Jun N-terminal kinases

MDM2:

Murine double minue-2

NF-κB:

Nuclear factor kappa B

NF-κB:

Nuclear factor-kappa B

NQO-1:

NADPH-quinone oxidoreductase-1

Nrf-2:

Nuclear factor E2-related factor 2

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

SRXN1:

Sulfiredoxin 1

STZ:

Streptozotocin

T2D:

Type 2 diabetes

TGF-B:

Transforming growth factor-beta

UDP:

Uridine 5′-diphospho-glucuronosyltransferas

UGT:

UDP-glucuronosyltransferase

WHO:

World health organization

β-TrCP:

Beta-transducin repeats-containing protein

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Authors and Affiliations

  1. Chitkara College of Pharmacy, Chitkara University, Chandigarh, Punjab, India

    Amit Gupta, Tapan Behl & Aayush Sehgal

  2. Amity Institute of Pharmacy, Amity University, Noida, Haryana, India

    Saurabh Bhatia

  3. Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Sultanate of Oman

    Saurabh Bhatia

  4. R.S. Memorial College of Pharmacy, Panipat, Haryana, India

    Dharmender Jaglan

  5. Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania

    Simona Bungau

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  1. Amit Gupta
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  2. Tapan Behl
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AG and TB: Conceived the idea and wrote the paper; AS: Figure Work; SBH and DG: Literature Survey; SB: Proof Read.

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Gupta, A., Behl, T., Sehgal, A. et al. Therapeutic potential of Nrf-2 pathway in the treatment of diabetic neuropathy and nephropathy. Mol Biol Rep 48, 2761–2774 (2021). https://doi.org/10.1007/s11033-021-06257-5

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