肾脏纤维化是CKD进展到ESRD的共同途径，肾小管上皮细胞损伤是启动和推进纤维化的关键环节。我们前期揭示线粒体稳态失衡是肾小管上皮细胞损伤的起始事件，深入探讨该机制有望为干预肾脏纤维化提供新的靶标。前期结果进一步发现，Lon蛋白酶的表达/活性下降与肾脏纤维化进展密切相关；Lon蛋白酶负责线粒体蛋白质量控制，参与维持线粒体的稳态。由此设想，Lon蛋白酶功能障碍引发线粒体稳态失衡是肾脏纤维化进展的核心机制；拟利用肾小管上皮细胞条件性Lon蛋白酶敲除及转基因小鼠和细胞模型，明确Lon蛋白酶在维持线粒体稳态、阻断肾脏纤维化发生中的作用及分子机制。在此基础上，我们还发现转录因子Oct-1和去乙酰化酶Sirt3分别调控Lon蛋白酶的转录表达及乙酰化修饰的活性；故结合体内模型进一步探讨Lon蛋白酶的调控机制，及其在肾脏纤维化中的意义。本研究将丰富肾脏纤维化发生的线粒体稳态学说，为向临床转化提供理论依据。

Renal fibrosis is the final common pathway to end-stage renal disease. Understanding the mechanisms of renal fibrosis is essential in establishing novel therapeutic strategies for the prevention or arrest of progressive kidney diseases. Among the renal residential cells, tubular epithelial are the principal effectors in initiating and mediating renal fibrosis. Our previous study showed that impaired mitochondrial homeostasis was the early event in tubular epithelial cell injury. However, the mechanism involved in the impaired mitochondrial homeostasis remains unclear. Our preliminary data showed that mitochondrial Lon protease expression/activity were significantly down-regulated in the kidney from unilateral ureteral obstruction (UUO) mice and patients with CKD and in the cultured renal tubular epithelial cells stimulated with TGF-beta or angiotension II (Ang II). Transcription factor Oct-1, as transcriptional repressor for Lon protease, inhibited its expression, whereas mitochondrial deacetylase Sirt3 regulated the activity by deacetylation of Lon protease. Therefore, we hypothesized that Lon protease dysfunction induced the impaired mitochondrial homeostasis, which play an important role in the mechanism of renal fibrosis. To test this hypothesis, we determine the effect of Lon protease on maintaining mitochondrial homeostasis and blocking renal fibrosis by using the renal tubular epithelial Lon protease or Oct-1 conditional knockout mice and transgenic mice and cultured renal tubular epithelial cell models. We will investigate the role of transcription factor Oct-1 and deacetylase Sirt3 in the transcriptional and post-transcriptional regulation of Lon protease. The present study will not only enrich the theory of mitochondrial homeostasis and the occurrence of renal fibrosis, also provide the new targets for intervention in renal fibrosis.