Melatonin prevents diabetes‐induced nephropathy by modulating the AMPK/SIRT1 axis: Focus on autophagy and mitochondrial dysfunction

Melatonin prevents diabetes‐induced nephropathy by modulating the AMPK/SIRT1 axis: Focus on autophagy and mitochondrial dysfunction

Impaired nutrient sensing mechanisms such as AMPK/silent information regulator type 1 (SIRT1) axis and autophagy in renal cells upon chronic diabetic condition accelerate renal injury and upregulating these mechanisms has been reported to prevent renal damage. Melatonin, a neuroendocrine agent, also...

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Published in:Cell biology international Vol. 46; no. 12; pp. 2142 - 2157
Main Authors: Siddhi, Jain, Sherkhane, Bhoomika, Kalavala, Anil Kumar, Arruri, Vijay, Velayutham, Ravichandiran, Kumar, Ashutosh
Format: Journal Article
Language:English
Published: London Wiley Subscription Services, Inc 01-12-2022
Subjects:
AMPK
Autophagy
Biosynthesis
Diabetes
Diabetes mellitus
Diabetic nephropathy
Glucose
kidney
Lysates
Melatonin
Mitochondria
Nephropathy
Oxidative stress
Renal function
SIRT1 protein
Streptozocin
Supplements
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Summary:Impaired nutrient sensing mechanisms such as AMPK/silent information regulator type 1 (SIRT1) axis and autophagy in renal cells upon chronic diabetic condition accelerate renal injury and upregulating these mechanisms has been reported to prevent renal damage. Melatonin, a neuroendocrine agent, also possess antioxidant and AMPK modulatory effect. In the current study, the protective effect of melatonin against diabetic renal injury was assessed in streptozotocin‐induced diabetic nephropathy model and in in vitro model of high‐glucose‐induced tubular injury. Melatonin (3 and 10 mg/kg) was administered for 28 days after 4 weeks of diabetes induction in Sprague–Dawley rats. For in vitro model, the NRK‐52E cells were co‐incubated with high glucose and melatonin (25 and 50 μM). Melatonin supplementation abrogated the diabetes‐induced renal injury and improved renal function in diabetic rats. Immunoblot analysis of renal tissue lysates revealed improved expression of AMPK, as well as upregulated the expression of nuclear factor erythroid 2‐related factor 2, SIRT1, PGC‐1α, TFAM and enhanced autophagy upon melatonin treatment in diabetic rats. Likewise, melatonin treatment in high glucose exposed NRK‐52E cells improved expression of AMPK, enhanced mitochondrial biogenesis and positively modulated autophagy. However, these effects were repressed upon inhibition of AMPK activity in NRK‐52E cells by treatment of Compound‐C, suggesting that the protective effects of melatonin were mainly mediated through activation of AMPK. These results suggest that melatonin might mediate the renoprotective effect by upregulating the AMPK/SIRT1 axis, enhancing the autophagy and mitochondrial health in DIabetic Nephropathy. Highlights 1. Melatonin improves renal function in streptozotocin‐induced diabetic nephropathy model. 2. Melatonin upregulates AMPK/SIRT1 axis, mitochondrial biogenesis and autophagy in diabetic kidney and in high‐glucose‐exposed NRK‐52E cells. 3. Inhibition of AMPK prevents protective effect of melatonin in NRK‐52E cells.
Bibliography:Jain Siddhi and Bhoomika Sherkhane contributed equally to this study.
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ISSN:1065-6995
1095-8355
DOI:10.1002/cbin.11899