Liu Jin-Rui, Cai Guang-Yan, Ning Yi-Chun, Wang Jing-Chao, Lv Yang, Guo Ya-Nan, Fu Bo, Hong Quan, Sun Xue-Feng, Chen Xiang-Mei
Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Chinese PLA General Hospital, Beijing 100853, China.
Renal Transplant Division, Department of Nephrology, Zhengzhou No. 7 People's Hospital, Zhengzhou 450017, Henan, China.
Aging (Albany NY). 2020 Aug 27;12(18):18052-18072. doi: 10.18632/aging.103591.
Glomerulosclerosis and renal interstitial fibrosis occur with the aging kidney. In this study, we examined the expression of miR-21, peroxisome proliferator-activated receptor(PPARα), hypoxia-inducible factor(HIF-1α) in the kidney of 3-month-old rats fed ad libitum (YAL), 24-month-old rats fed ad libitum (OAL) and 24-month-old rats subjected to a 70% calorie-restricted diet for 8 months (OCR). We found long-term caloric restriction (CR) ameliorated aging and aging-related fibrosis. CR ameliorated the increment of miR-21 and HIF-1α, as well as the decrement of PPARα in old ad libitum group. Human proximal tubular cells (HPTCs) presented phenotypes of senescence and epithelial to mesenchymal transition (EMT) under high-glucose conditions, in which senescence occurred earlier than EMT. Senescent cells secreted extracellular vesicles (EVs) which contained miR-21 into the recipient cells. Inhibiting miR-21 of donor cells prevented the occurrence of EMT in recipient cells. In addition, miR-21 induced EMT through targeting PPARα protein and consequently enhancing HIF-1α expression, although other pathways cannot be ruled out. These findings demonstrated that miR-21-containing EVs derived from the senescent cells could facilitate EMT of HPTCs via PPARα-HIF-1α signaling pathway. Long-term caloric restriction and caloric restriction mimetics alleviated aging-related-fibrosis of kidney through downregulation of miR-21.
肾小球硬化和肾间质纤维化随肾脏衰老而发生。在本研究中，我们检测了自由进食的3月龄大鼠（YAL）、自由进食的24月龄大鼠（OAL）以及接受70%热量限制饮食8个月的24月龄大鼠（OCR）肾脏中miR-21、过氧化物酶体增殖物激活受体（PPARα）、缺氧诱导因子（HIF-1α）的表达。我们发现长期热量限制（CR）改善了衰老及衰老相关的纤维化。CR改善了自由进食老年组中miR-21和HIF-1α的增加以及PPARα的减少。人近端肾小管细胞（HPTCs）在高糖条件下呈现衰老和上皮-间质转化（EMT）表型，其中衰老比EMT更早发生。衰老细胞分泌含有miR-21的细胞外囊泡（EVs）进入受体细胞。抑制供体细胞中的miR-21可防止受体细胞中EMT的发生。此外，miR-21通过靶向PPARα蛋白并因此增强HIF-1α表达来诱导EMT，尽管不能排除其他途径。这些发现表明，来自衰老细胞的含miR-21的EVs可通过PPARα-HIF-1α信号通路促进HPTCs的EMT。长期热量限制和热量限制模拟物通过下调miR-21减轻了肾脏衰老相关的纤维化。
