Klotho调控铁死亡在ADPKD囊肿发生发展中的作用及机制研究

常染色体显性多囊肾病（ADPKD）是发病率最高的致死性遗传性肾脏病，其发病机制未完全阐明，尚无有效治疗手段。我们前期研究提示Klotho蛋白在ADPKD肾组织中较其它慢性肾衰模型明显低表达，其机制可能与其启动子区域甲基化水平升高相关。已有研究表明Klotho表达与铁死亡水平负相关，而阻断铁死亡可抑制ADPKD囊肿生长。据此，我们推测多囊蛋白突变通过表观遗传修饰介导Klotho下调抑制细胞铁死亡参与ADPKD囊肿发生发展。本项目将采用外源性Klotho蛋白、铁死亡特异性激动剂和抑制剂处理囊肿上皮细胞，通过脂质过氧化物染色、免疫共沉淀等手段探索Klotho对细胞铁死亡的调控作用及机制。并在多囊肾小鼠模型中观察外源性给予Klotho对铁死亡过程关键调控蛋白及囊肿发生发展的影响，该研究将为进一步揭示ADPKD发病机制并寻找新的治疗靶标提供理论依据与实验基础。

Autosomal dominant polycystic kidney disease (ADPKD) is the most common lethal hereditary kidney disease. Its pathogenesis is not fully elucidated and there is no effective treatment. Our previous studies suggest that Klotho protein is significantly lower expressed in ADPKD kidney tissue than other chronic renal failure models, and its mechanism may be related to the increased methylation level of its promoter region. Previous studies have shown that Klotho expression is inversely related to ferroptosis activity, and blocking ferroptosis can inhibit ADPKD cyst growth. Based on this, we speculate that Klotho may participate in the development of ADPKD cysts by inhibiting cell ferroptosis process. This study will use exogenous Klotho protein, ferroptosis-specific agonists and inhibitors to treat cyst epithelial cells, and explore the regulatory effect and mechanism of Klotho on ferroptosis by means of lipid peroxide staining and CO-IP. Besides, we will observe whether the exogenous Klotho have the effect of administrating key regulator of ferroptosis and delaying the development of cysts in polycystic kidney mouse models. This study will further reveal The pathogenesis of ADPKD and provide theoretical and experimental basis for new therapeutic targets.