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Melatonin prevents diabetes-induced nephropathy by modulating the AMPK/SIRT1 axis: Focus on autophagy and
Jain Siddhi1, Bhoomika Sherkhane1, Anil Kumar Kalavala2
1Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India.
Abstract:
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.
Insights
Melatonin protects against diabetic kidney disease by enhancing nutrient sensing pathways like AMPK/SIRT1 and autophagy. This study shows melatonin improves kidney function and cellular health in diabetic models.
Area of Science:
- Nephrology
- Endocrinology
- Cell Biology
Background:
- Diabetic kidney disease involves impaired nutrient sensing (AMPK/SIRT1) and autophagy.
- Melatonin, an antioxidant, may modulate these pathways.
- Targeting these mechanisms could prevent renal damage.
Purpose of the Study:
- To investigate melatonin's protective effects against diabetic renal injury.
- To assess melatonin's impact on AMPK/SIRT1 axis and autophagy in diabetic nephropathy.
- To elucidate the role of AMPK activation in melatonin's renoprotective action.
Main Methods:
- Streptozotocin-induced diabetic nephropathy model in rats.
- In vitro high-glucose-induced tubular injury model using NRK-52E cells.
- Melatonin administration and AMPK inhibition (Compound-C) followed by molecular analysis.
Main Results:
- Melatonin treatment improved renal function and attenuated injury in diabetic rats.
- Melatonin upregulated AMPK, SIRT1, PGC-1α, TFAM, and enhanced autophagy in vivo and in vitro.
- Inhibition of AMPK reversed melatonin's protective effects in NRK-52E cells.
Conclusions:
- Melatonin exerts renoprotective effects in diabetic nephropathy.
- These effects are mediated by the upregulation of the AMPK/SIRT1 axis, autophagy, and mitochondrial health.
- Melatonin shows therapeutic potential for managing diabetic kidney disease.
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