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Melatonin Improves Endoplasmic Reticulum Stress-Mediated IRE1α Pathway in Zücker Diabetic Fatty Rat

Department of Pharmacology, Biohealth Institute and Neurosciences Institute, School of Medicine, University of Granada, 18016 Granada, Spain
Team of Cellular and Molecular Physiopathology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene, El Alia, Algiers 16111, Algeria
Department of Nutrition and Bromatology, School of Pharmacy, University of Granada, 18071 Granada, Spain
Bioactive Molecule Valorization Research Unit, Higher Institute of Applied Biology of Medenine, University of Gabes, Gabes 4119, Tunisia
Biosanitary Research Institute of Granada (ibs. GRANADA), University Hospital of Granada, 18016 Granada, Spain
Author to whom correspondence should be addressed.
Academic Editor: Noelia Duarte
Pharmaceuticals 2021, 14(3), 232;
Received: 15 February 2021 / Revised: 3 March 2021 / Accepted: 4 March 2021 / Published: 8 March 2021
Obesity and diabetes are linked to an increased prevalence of kidney disease. Endoplasmic reticulum stress has recently gained growing importance in the pathogenesis of obesity and diabetes-related kidney disease. Melatonin, is an important anti-obesogenic natural bioactive compound. Previously, our research group showed that the renoprotective effect of melatonin administration was associated with restoring mitochondrial fission/fusion balance and function in a rat model of diabesity-induced kidney injury. This study was carried out to further investigate whether melatonin could suppress renal endoplasmic reticulum (ER) stress response and the downstream unfolded protein response activation under obese and diabetic conditions. Zücker diabetic fatty (ZDF) rats and lean littermates (ZL) were orally supplemented either with melatonin (10 mg/kg body weight (BW)/day) (M–ZDF and M–ZL) or vehicle (C–ZDF and C–ZL) for 17 weeks. Western blot analysis of ER stress-related markers and renal morphology were assessed. Compared to C–ZL rats, higher ER stress response associated with impaired renal morphology was observed in C–ZDF rats. Melatonin supplementation alleviated renal ER stress response in ZDF rats, by decreasing glucose-regulated protein 78 (GRP78), phosphoinositol-requiring enzyme1α (IRE1α), and ATF6 levels but had no effect on phospho–protein kinase RNA–like endoplasmic reticulum kinase (PERK) level. In addition, melatonin supplementation also restrained the ER stress-mediated apoptotic pathway, as indicated by decreased pro-apoptotic proteins phospho–c–jun amino terminal kinase (JNK), Bax, and cleaved caspase-3, as well as by upregulation of B cell lymphoma (Bcl)-2 protein. These improvements were associated with renal structural recovery. Taken together, our findings revealed that melatonin play a renoprotective role, at least in part, by suppressing ER stress and related pro-apoptotic IRE1α/JNK signaling pathway. View Full-Text
Keywords: melatonin; endoplasmic reticulum stress; diabesity; kidney melatonin; endoplasmic reticulum stress; diabesity; kidney
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MDPI and ACS Style

Aouichat, S.; Navarro-Alarcon, M.; Alarcón-Guijo, P.; Salagre, D.; Ncir, M.; Zourgui, L.; Agil, A. Melatonin Improves Endoplasmic Reticulum Stress-Mediated IRE1α Pathway in Zücker Diabetic Fatty Rat. Pharmaceuticals 2021, 14, 232.

AMA Style

Aouichat S, Navarro-Alarcon M, Alarcón-Guijo P, Salagre D, Ncir M, Zourgui L, Agil A. Melatonin Improves Endoplasmic Reticulum Stress-Mediated IRE1α Pathway in Zücker Diabetic Fatty Rat. Pharmaceuticals. 2021; 14(3):232.

Chicago/Turabian Style

Aouichat, Samira, Miguel Navarro-Alarcon, Pablo Alarcón-Guijo, Diego Salagre, Marwa Ncir, Lazhar Zourgui, and Ahmad Agil. 2021. "Melatonin Improves Endoplasmic Reticulum Stress-Mediated IRE1α Pathway in Zücker Diabetic Fatty Rat" Pharmaceuticals 14, no. 3: 232.

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