Tsc1调控糖酵解介导肾间质纤维化的作用机制

Renal interstitial fibrosis is a key factor in the progression of chronic kidney disease (CKD). Energy reprogram to glycolysis is closely related to the development of CKD. As an important negative regulatory factor of mTORC1 signal，tuberous sclerosis complex 1 (Tsc1) is also the key regulatory point of glycolysis. Therefore, the hypothesis is that Tsc1 could mediate the progress of renal interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells. This research project will be set up as follows. First of all, in vitro and in vivo models of renal interstitial fibrosis will be established. Then we will analyze the changes of Tsc1 in the progress of renal interstitial fibrosis and find the relationship of glycolysis and Tsc1. Next, we will compare the glycolysis level and the degree of fibrosis in kidneys between proximal tubular epithelial cells-Tsc1 specific knockout mice and control mice to explore the role and mechanism of Tsc1 in renal interstitial fibrosis. This study will be helpful to further understand the pathophysiological mechanism of renal interstitial fibrosis and provide theoretical basis for design of new preventive and therapeutic strategies.

肾间质纤维化是慢性肾脏病（chronic kidney disease, CKD）进展的关键因素。细胞能量代谢重组如糖酵解的增强和线粒体的损伤与CKD的进展密切相关。作为mTORC1信号重要的负性调控因子，Tsc1也是糖酵解的关键调控点。由此提出科学假说：Tsc1可通过调节肾小管上皮细胞的糖酵解介导肾间质纤维化的发生和发展。本项目拟从体外和体内分别进行描述性和干预性研究，以原代小管上皮细胞和肾间质纤维化模型为研究对象，并以Tsc1为研究靶点，探讨正常和疾病状态下Tsc1和糖酵解的关系，并进一步揭示其在肾间质纤维化中的作用机制。本项目试图阐明肾小管上皮细胞Tsc1是否是肾间质纤维化的关键调控蛋白，并明确肾小管上皮细胞的糖酵解是否受Tsc1的调控，探讨Tsc1调控的糖酵解是否能成为延缓CKD进展的治疗靶点。本研究有助于人们深入认识肾间质纤维化的病理生理机制，为未来设计新的防治方案提供理论依据。

肾间质纤维化是慢性肾脏病（chronic kidney disease, CKD）进展的关键因素。细胞能量代谢重组如糖酵解的增强和线粒体的损伤与CKD的进展密切相关。作为mTORC1信号重要的负性调控因子，Tsc1也是糖酵解的关键调控点。本项目从体外和体内分别进行描述性和干预性研究，以原代小管上皮细胞和肾间质纤维化模型为研究对象，并以Tsc1为研究靶点，探讨正常和疾病状态下Tsc1和糖酵解的关系，并进一步揭示其在肾间质纤维化中的作用机制。本研究利用单侧输尿管梗阻（UUO）模型诱导肾脏小管上皮细胞mTORC1信号的活化，同时引起小管上皮细胞的增殖和糖酵解关键酶的上调。雷帕霉素阻断mTORC1信号的活化能够抑制糖酵解和小管上皮细胞的增殖。此外，下调小管上皮细胞Tsc1的表达能够增强糖酵解的水平。小管上皮细胞特异性敲除Tsc1小鼠可表现为肾脏的增大，伴有小管上皮细胞的增殖、囊腔的形成和小管间质纤维化以及糖酵解的增强。用糖酵解抑制剂2-DG治疗该小鼠模型可显著减轻肾小管上皮细胞的增殖、囊腔的形成和肾脏纤维化。因此，我们的研究提示，Tsc1相关的mTORC1信号通过调控小管上皮细胞的糖酵解促进肾间质纤维化。本研究有助于人们深入认识肾间质纤维化的病理生理机制，为未来设计新的防治方案提供理论依据。