Department of Geriatric Endocrinology, Chinese PLA General Hospital, National Clinical Center of Geriatric Medicine, Beijing 100853, P.R. China.
Outpatient Department, Chinese PLA General Hospital, Beijing 100853, P.R. China.
Mol Med Rep. 2019 Feb;19(2):1318-1330. doi: 10.3892/mmr.2018.9708. Epub 2018 Nov 29.
Mitochondrial homeostasis is a highly regulated process that serves a critical role in the maintenance of renal structure and function. The growing interest in the field of mitochondrial homeostasis promises to provide more information regarding the mechanisms involved in diabetic renal fibrosis, and aid in the development of novel strategies to combat the disease. In the present study, the effects of melatonin on renal damage in mice with diabetes were evaluated and the underlying mechanisms were investigated. Cellular apoptosis was determined using TUNEL assay and western blotting. Mitochondrial function was measured using fluorescence assay and western blotting. The results indicated that diabetic renal fibrosis was associated with 5'adenosine monophosphate‑activated protein kinase (AMPK) downregulation. However, melatonin administration rescued AMPK activity, reduced diabetic renal fibrosis, alleviated glomerular apoptosis and preserved kidney function. The functional experiments demonstrated that melatonin‑induced AMPK activation enhanced peroxisome proliferator‑activated receptor γ coactivator 1‑α (PGC1α) expression, sustained mitochondrial function and blocked mitochondrial apoptosis, leading to protection of the glomerulus against glucotoxicity. However, loss of AMPK and PGC1α negated the protective effects of melatonin on mitochondrial homeostasis, glomerular survival and diabetic renal fibrosis. In summary, the present study revealed that melatonin rescued impaired mitochondrial function and reduced glomerular apoptosis in the context of diabetic renal fibrosis by activating the AMPK/PGC1α pathway.
线粒体稳态是一个高度调控的过程，对维持肾脏结构和功能起着至关重要的作用。目前，人们对线粒体稳态领域的研究兴趣日益浓厚，有望提供更多有关糖尿病肾纤维化相关机制的信息，并有助于开发新的策略来对抗该疾病。在本研究中，评估了褪黑素对糖尿病小鼠肾脏损伤的作用，并探讨了其潜在机制。采用 TUNEL 检测和 Western blot 法检测细胞凋亡。采用荧光检测和 Western blot 法测定线粒体功能。结果表明，糖尿病肾纤维化与 5' 腺苷一磷酸激活蛋白激酶（AMPK）下调有关。然而，褪黑素给药可恢复 AMPK 活性，减少糖尿病肾纤维化，减轻肾小球细胞凋亡并维持肾功能。功能实验表明，褪黑素诱导的 AMPK 激活增强过氧化物酶体增殖物激活受体 γ 共激活因子 1-α（PGC1α）的表达，维持线粒体功能并阻断线粒体凋亡，从而保护肾小球免受糖毒性。然而，AMPK 和 PGC1α 的缺失则消除了褪黑素对线粒体稳态、肾小球存活和糖尿病肾纤维化的保护作用。综上所述，本研究揭示了褪黑素通过激活 AMPK/PGC1α 通路，挽救了糖尿病肾纤维化中受损的线粒体功能并减少了肾小球细胞凋亡。
