适当运动能延缓糖尿病肾病（DKD）进展，但机制尚不清楚。我们既往研究显示，小鼠骨骼肌特异性过表达PGC-1α(mPGC-1α) 可模拟运动状态，刺激肌肉释放多种肌肉因子进入血液，作用于肾脏并减轻肾小管间质纤维化。前期研究中，我们观察到mPGC-1α可防止糖尿病导致的肾小球硬化及足细胞损伤，肌肉因子IL-15可减轻高糖引起的足细胞线粒体损伤，提示IL-15是介导运动延缓DKD进展的重要介质，并通过维护线粒体功能，改善足细胞的功能障碍。本项目拟采用mPGC-1α转基因与db/db杂交的2型糖尿病小鼠、STZ诱导的1型糖尿病小鼠和体外培养的足细胞，利用mRNA array、ChIP、基因沉默等技术，结合线粒体形态及呼吸功能实时检测，从体内和体外实验验证我们的假设，并探讨IL-15通过抑制HDAC酶、上调OPA1改善足细胞线粒体动态平衡的机制。本研究将为临床采用肌肉因子或运动疗法防治DKD提供依据

Exercises can improve the prognosis of diabetic kidney disease (DKD), however, the underlying mechanism remains unclear. We have demonstrated that muscle-specific overexpression of PGC-1α (mPGC-1α) in mouse mimics persistent exercises and ameliorates renal interstitial fibrosis. In preliminary studies, we also found that glomerulosclerosis and podocyte mitochondrial damage induced by diabetes were limited in mPGC-1α mice. Since interlukin-15(IL-15), one of myokines upregulated by mPGC-1α, exhibited the similar protective effects on the cultured podocytes, we hypothesize that IL-15 mediates the muscle-kidney communication protecting against podocyte mitochondrial injury. In this proposal, we will study the mPGC-1α mice with diabetes induced by crossing with db/db mice or STZ injection, and investigate the mechanism by which IL-15 maintains podocyte mitochondrial homeostasis. We also plan to examine if Optic Atrophy 1(OPA1) up-regulation induced by HDAC inhibition mediates the protective effects of IL-15. The results of our proposal will help us to understand how exercise ameliorates diabetic kidney disease via muscle-kidney communication and will provide theoretic basis to prevent the development of DKD with exercise or IL-15 therapies.