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

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.

Autophagy and its therapeutic potential in diabetic nephropathy

“…The impairment of autophagy in diabetic podocytes as evidenced by the decreased expression of autophagy-related proteins (beclin1, LC3II/I, Atg12, Atg7, etc.) and the accumulation of the autophagic substrate p62 ( 40 , 67 ) exacerbates the loss of podocytes with the help of the increased cellular lipid accumulation, oxidative stress, and inflammation ( 11 , 41 ). Knockout of the Atg5 in podocytes has been reported to cause glomerular lesions accompanied by podocyte loss and albuminuria ( 68 ).…”

“…It has been shown that AMPK and autophagy are deactivated in the diabetic kidney accompanied by proteinuria and renal pathological alterations ( 11 , 45 , 56 , 108 ). As shown in Figure 2 , AMPK can phosphorylate ULK1 at Ser317 and Ser377 to directly initiate autophagy ( 109 , 110 ) or indirectly promote autophagy by blocking mTORC1 to release ULK1 through phosphorylating tuberous sclerosis complex 2 (TSC2) and raptor, the critical mTORC1-binding subunit ( 111 ), which benefits to hinder the progression of DN ( 112 ).…”

“…However, the serious side effect of rapamycin limits its use in long-term clinical treatment ( 75 ). Animal studies showed that melatonin, resveratrol, and vitamin D analogs prevent DN by modulating AMPK-regulated autophagy ( 11 , 35 , 53 , 162 ), which may be the candidate drug for treating DN in the clinic.…”

“…Autophagy normally is activated to degrade impaired organelles or misfolded proteins as a recycling response to nutrition deprivation or starvation (10). The metabolic disorder manifested as persistent high blood glucose and lipids causes a state of overnutrition and suppresses autophagy in diabetic renal cells (11)(12)(13), while promoting autophagy lessens renal injury in diabetes (14,15). All these clues suggest that activating autophagy may be a novel therapeutic target to prevent DN and shed light on treating DN based on the balance of autophagy.…”

Melatonin ameliorates the adrenal and pancreatic alterations in streptozotocin-induced diabetic rats: Clinical, biochemical, and descriptive histopathological studies

“…The rats were then divided into four groups of 10 each: Group I, a normal control group (n = 10) that was given regular rat food and water; Group II, the melatonin group (MT; n = 10) received an IP injection of melatonin, 10 mg/kg/day, for 4 weeks. The melatonin was dissolved in DMSO (1%, w/v) prior to injection (24)(25)(26)(27)(28). Group III, the diabetes STZ group (n = 10), were fasted the previous night for 12 h before inducing diabetes.…”