基于单核巨噬细胞激活的daintain/p38MAPK通路研究醛固酮诱导的肾间质纤维化的新机制

肾间质纤维化（RIF）是慢性肾功衰竭的共同通路和死亡原因，多认为与炎症导致的肾间质固有细胞的增生密切相关。醛固酮（ALD）可通过诱发肾间质炎症而促进肾间质纤维化，但机制不清。我们的前期研究结果表明：在肾间质成纤维细胞系中，在ALD的诱导下，大炎肽（daintain）表达明显升高；并证实了大炎肽参与肾间质炎症的发生。但是大炎肽与肾间质纤维化的关系，迄今国内外尚无报道。因此，我们提出假设：在慢性肾脏病（CKD）中，升高的醛固酮可通过巨噬细胞募集后使大炎肽表达水平升高和/或通过Ca2+激活大炎肽，而促进肾间质纤维化。我们将应用细胞系，动物模型及临床标本，结合荧光素酶报告基因、免疫共沉淀、免疫荧光等实验方法，阐明醛固酮致肾间质纤维化的机制，本课题将首次建立醛固酮诱导肾间质纤维化的细胞内信号网络，为肾间质纤维化的发生发展机制提出新的理论，为肾间质纤维化的CKD 治疗提供潜在新靶点。

Renal interstitial fibrosis is commom path and death causes, which mechanism is mainly contribute to renal interstitial proliferation caused by inflammation. Aldosterone plays a vital role in regulation of renal interstitial fibrosis induced by renal interstitial cells inflammation, but the mechanism remains unclear. In our preliminary studies, we found that daintain are upregulated in the renal interstitial fibroblasts, and daintain could induce the renal interstitial fibrosis. Therefore, we hypothesize that aldosterone upregulates Daintain expression via calcium and mononuclear macrophages accumulation in renal interstitial fibrosis in chronic renal diseases. We will use gene-chip analysis, laser confocal imaging analysis, ,Luciferase reporter gene vector，molecular biology techniques and vascular function studies to test our hypothesis and will determine the mechanisms by which aldosterone play very important role in regulation of renal interstitial fibrosis. Our findings will provide new insight to regulation of vascular function and may also provide potential therapeutic targets for hypertension.