Cathepsin S在肾脏纤维化中的作用与机制

肾小管上皮细胞间充质转分化（EMT）是肾脏纤维化的重要事件之一。我们前期研究表明小管上皮细胞（TECs）表达组织蛋白酶Cathepsin S（CatS），并激活TGF-β/Smads信号通路，CatS缺失可抑制EMT，且依赖于其在TECs的表达和酶活性。此外，CatS基因敲除小鼠的肾脏纤维化程度明显高于野生型，提示CatS的促纤维化作用。但其机制尚不清楚。本项目拟利用CatS缺失和TECs特异性敲除CatS小鼠的慢性肾病模型，进一步证实CatS对EMT和纤维化的作用；分别应用上述原代TECs，沉默HK-2细胞CatS和药物改变酶活性等方法，探讨TGF-β作用下CatS对EMT的调控作用，研究CatS介导Smads信号通路的关键分子；前瞻性观察CatS与慢性肾脏病的联系。本研究有助于揭示CatS调控EMT促进肾脏纤维化的作用和机制，为临床应用CatS抑制剂防治纤维化提供科学依据。

Fibrosis is the final common manifestation of chronic kidney disease (CKD), which eventually progresses towards end-stage renal disease (ESRD). Emerging evidence suggests an important role of cysteinyl cathepsin (CatS) in human biology. On-going clinical trials to target CatS with small molecule inhibitors suggest a potential in mitigating fibrosis in kidney. This application proposes innovative roles of CatS in EMT, TGF-β signaling and renal fibrosis: 1).Identifies novel role of CatS in mediating TGF-β downstream signaling, phosphorylated p-Smad-2/3 translocation between the cytoplasm and nuclei, and associated molecular mechanisms; 2). Uses a unique set of gene knockout mice and renal tubular epithelial cell-conditional knockout mice that lack the expression of CatS to test its role in TGF-β signaling, EMT and renal fibrosis and; 3).Investigates the correlation between CatS expression and pathology and clinical outcome in CKD; 4). Uses specific small molecule inhibitor to selectively block the activity of CatS in post-UUO fibrosis to extend the value of translational medicine of this application.