基于AIF-1炎症信号通路研究醛固酮诱导慢性肾脏病相关血管钙化机制

Although increasing evidences show that aldosterone receptor antagonist can obviously inhibit chronic kidney disease (CKD) related vascular calcification, it is strictly limited in CKD patients due to the side effects of hyperkalemia. It is very important to explore the mechanism of aldosterone-induced vascular calcification. In the prophase research of relationship between aldosterone/AIF-1 and renal interstitial fibrosis, applicants proved that aldosterone exerts effect with a AIF-1-dependent pathway. Based on the effect of aldosterone in vascular calcification, applicants speculate aldosterone promote vascular calcification with a AIF-1-dependent pathway. However, whether AIF-1 is associated with vascular calcification is still unclear. Therefore, applicants put forward aldosterone induces vascular calcification by AIF-1 signal pathways, and attempt to demonstrate that aldosterone could activate AIF-1/NF-κB and AIF-1/mTORC1 signals, inducing the interactions of mononuclear macrophages, endothelial cells and vascular smooth muscle cells, promoting vascular smooth muscle cells inflammation, differentiation, secretion of matrix vesicles and calcification in the cell and animal models respectively.Through this study project, we hope to confirm that aldosterone can induce CKD related vascular calcification via inflammatory signaling pathway of AIF-1, provide a new theoretical basis for prevention of vascular calcification.

目前已经证实醛固酮受体拮抗剂能抑制CKD相关血管钙化，但是由于其高钾血症的副作用使其在CKD患者中应用受到严格限制，积极探讨醛固酮诱导血管钙化的确切机制具有重要意义。申请者在研究醛固酮/AIF-1与肾间质纤维化关系时发现，醛固酮主要通过AIF-1依赖途径发挥效应。同时基于醛固酮在血管钙化中的作用，以及在AIF-1转基因小鼠体内发现AIF-1表达与血管钙化相关，申请者提出醛固酮也可能通过AIF-1参与血管钙化，但尚无相关文献报道。因此申请者提出醛固酮通过AIF-1信号诱导血管钙化，拟通过体内和体外实验探讨醛固酮激活AIF-1/NF-κB和AIF-1/mTORC1信号诱导单核巨噬细胞，血管内皮和平滑肌细胞相互作用，诱发平滑肌细胞炎症、分化、形成和分泌基质小泡，钙化的机制。本项目将首次证实醛固酮以AIF-1依赖方式激活CKD相关血管钙化的信号网络，为防治血管钙化提供新的理论依据和潜在治疗靶点。

目前已经证实醛固酮受体拮抗剂能抑制CKD相关血管钙化，但是由于其高钾血症的副作用使其在CKD患者中应用受到严格限制，积极探讨醛固酮诱导血管钙化的确切机制具有重要意义。申请者在研究醛固酮/AIF-1与肾间质纤维化关系时发现，醛固酮主要通过AIF-1依赖途径发挥效应。同时基于醛固酮在血管钙化中的作用，以及在AIF-1转基因小鼠体内发现AIF-1表达与血管钙化相关，申请者提出醛固酮也可能通过AIF-1参与血管钙化，但尚无相关文献报道。因此申请者提出醛固酮通过AIF-1信号通路诱导血管钙化，拟通过体内和体外实验探讨醛固酮激活AIF-1/PI3K/AKT/NF-κB、AIF-1/NF-κB/MCP-1/CCR-2和AIF-1/mTOR信号通路诱导单核巨噬细胞，血管内皮和平滑肌细胞相互作用，诱发平滑肌细胞炎症、钙化的机制。本项目将首次证实醛固酮以AIF-1依赖方式激活CKD相关血管钙化的信号网络，为防治血管钙化提供新的理论依据和潜在治疗靶点。