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 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.

Renoprotective potential of myo-inositol on diabetic kidney disease: Focus on the role of the PINK1/Parkin pathway and mitophagy receptors.

Recent studies have emphasized the role of mitochondria in renal function as well as in renal injury. Poor mitochondrial quality control mechanisms including mitochondrial fusion, fission and mitophagy are major contributors for progression of diabetic renal injury. The current study is aimed to evaluate the protective role of myo-inositol (MI) against diabetic nephropathy (DN) by utilizing high glucose exposed NRK 52E cell and streptozotocin (STZ) induced DN model. MI supplementation (at doses 37.5 and 75 mg/kg) ameliorated albuminuria and enhanced the renal function as indicated significant improvement in urinary creatinine and urea levels. On the other hand, the western blot analysis of both in vitro and in vivo studies has revealed poor mitophagy in renal cells which was reversed upon myo-inositol treatment. Apart from targeting the canonical PINK1/Parkin pathway, we also focused on the role mitophagy receptors prohibitin (PHB) and NIP3-like protein (NIX). A significant reduction in expression of NIX and PHB2 was observed in renal tissue of diabetic control rats and high glucose exposed NRK 52E cells. Myo-inositol treatment resulted in positive modulation of PINK1/Parkin pathway as well as PHB2 and NIX. Myo-inositol also enhanced the mitochondrial biogenesis in renal tissue of diabetic rat by upregulating Nrf2/SIRT1/PGC-1α axis. The current study thus underlines the renoprotective effect myo-inositol, upregulation of mitophagy proteins and mitochondrial biogenesis upon myo-inositol treatment.