C/EBPα通过调节线粒体的功能参与糖尿病肾病发展的机制研究

Diabetic nephropathy (DN) is one of the leading causes of end-stage renal disease, and its incidence increased dramatically in recent years. Mitochondrial malfunction plays a critical role in the complex pathogenesis of DN, but its regulatory mechanism and related pathophysiological change is still not fully illustrated. In previous studies, we had found that the downregulation of C/EBPα could induce glomerulosclerosis deterioration, regulate the mitochondrial homeostasis and accelerate the development of DN. Therefore, we propose that C/EBPα could participate in the development of DN through regulating mitochondrial homeostasis. In order to reveal the pathogenesis of DN and provide us a new therapeutic target for DN, we will analyze the relationship between C/EBPα expression and the degree of renal and mitochondrial injury in DN patients, and then observe the expression of C/EBPα, mitochondrial lesions and their related-damage/repair cellular process (oxidative stress, inflammation, autophagy and apoptosis) of kidney in high glucose circumstance. Further, we will investigate the relationship between renal injury, mitochondrial defects and C/EBPα in DN mouse model, conditional knockout mouse model and C/EBPα overexpression or knockdown renal cell lines. Last, we will explore the regulatory mechanism of C/EBPα acetylation modification in DN mitochondrial homeostasis to seek the novel treatment target for DN.

糖尿病肾病(DN)是终末期肾病的重要病因，其发病率逐年升高。DN发生和进展机制复杂，线粒体功能异常在糖尿病肾损伤中起重要作用，然而线粒体损伤的调控机制及其所导致的病理改变尚不明确。课题组前期发现C/EBPα表达下调可加重肾小球硬化，参与DN线粒体功能调控，加速糖尿病肾脏损伤进展。因而，课题组提出C/EBPα可能通过调控线粒体功能参与DN的发展，为验证，拟分析DN患者中C/EBPα表达与肾损伤及线粒体损伤的关联；观察高糖对C/EBPα表达、线粒体损伤及相关损伤/修复过程(氧化应激、炎症、凋亡及自噬等)的影响；利用高糖刺激C/EBPα过表达/敲低的肾脏细胞，及条件性C/EBPα敲除小鼠DN模型，研究C/EBPα与肾脏损伤、线粒体稳态失衡之间的关系；探究C/EBPα乙酰化修饰对DN线粒体稳态影响，从而阐明C/EBPα对DN线粒体损伤的调控机制，为寻找DN的新治疗靶点提供理论依据。

CCAAT增强子结合蛋白（C/EBPs）调节多种的细胞分化及炎症因子表达，本课题组前期研究证实原发性肾小球肾炎患者C/EBPα水平下降且具有疾病差异性。因此，本课题组进一步探讨C/EBPα在肾小球和肾小管损伤中的作用及机制，发现C/EBPα足细胞特异性敲除可以减轻高脂联合STZ注射诱导的小鼠糖尿病肾病；C/EBPα相关核受体PPARγ激动剂通过调控lncRNA-AI838599表达改善小鼠糖尿病肾病；C/EBPα足细胞特异性敲除可以减轻小鼠衰老相关肾损伤；C/EBPα通过调控铁死亡关键基因ACSL4影响线粒体功能最终影响糖尿病肾病的发生发展。本项目完成了C/EBPα在糖尿病肾病及衰老相关肾损伤中的作用及机制探索，为改善肾脏损伤提供理论依据。本课题受资助以来，研究工作顺利，完成了预期结果，发表SCI论文4篇，核心2篇，待发表SCI论文2篇，培养硕士博士5人。