Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India.
Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Science, Florida A&M University, Tallahassee, Florida, USA.
Cell Biol Int. 2022 Dec;46(12):2142-2157. doi: 10.1002/cbin.11899. Epub 2022 Sep 10.
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.
在慢性糖尿病状态下，肾脏细胞中的营养感应机制（如 AMPK/沉默信息调节因子 1（SIRT1）轴和自噬）受损，据报道，上调这些机制可预防肾脏损伤。褪黑素是一种神经内分泌物质，具有抗氧化和 AMPK 调节作用。在本研究中，评估了褪黑素对链脲佐菌素诱导的糖尿病肾病模型和高糖诱导的肾小管损伤体外模型的保护作用。在诱导糖尿病 4 周后，给予 Sprague-Dawley 大鼠 28 天的 3 和 10mg/kg 褪黑素治疗。对于体外模型，NRK-52E 细胞与高葡萄糖和褪黑素（25 和 50μM）共孵育。褪黑素补充剂可消除糖尿病引起的肾脏损伤并改善糖尿病大鼠的肾功能。肾脏组织裂解物的免疫印迹分析显示，糖尿病大鼠中 AMPK 的表达得到改善，核因子红细胞 2 相关因子 2、SIRT1、PGC-1α、TFAM 的表达上调，自噬增强。同样，在高葡萄糖暴露的 NRK-52E 细胞中，褪黑素处理可改善 AMPK 的表达，增强线粒体生物发生并正向调节自噬。然而，在用 Compound-C 处理抑制 NRK-52E 细胞中的 AMPK 活性后，这些作用受到抑制，表明褪黑素的保护作用主要通过激活 AMPK 介导。这些结果表明，褪黑素可能通过上调 AMPK/SIRT1 轴、增强自噬和线粒体健康来介导糖尿病肾病的肾保护作用。
