NLRP3／STC1调控系膜细胞-足细胞Cross Talk介导的足细胞－巨噬细胞转分化在IgA肾病发病机制中的作用研究

低糖基化IgA1 分子沉积于肾脏组织是IgA肾病（IgAN）的重要特征，但其引起肾脏病理改变的机制尚不清楚。结合新近的研究和预实验结果，我们推断：低糖基化IgA1分子沉积可激活系膜细胞TGF-β通路分泌TNF-α等炎症因子，通过系膜细胞-足细胞Cross Talk一方面引起氧化应激反应导致足细胞凋亡，另一方面激活足细胞NLRP3信号通路使其合成巨噬细胞标记F4/80，发生足细胞-巨噬细胞转分化（PMT）吞噬多聚IgA1进而分泌大量炎症因子，导致肾脏纤维化引起IgAN病理改变。而STC1作为抗氧化剂能拮抗这一过程保护足细胞避免其发生PMT，减轻肾脏的病理改变。本项目将通过体外和体内实验，在系膜细胞、足细胞和NLRP3-/-及STC1-/-小鼠中验证该科学假说，以期加深对IgAN发病机制的了解，探索NLRP3抑制剂及STC1激动剂治疗IgAN的可行性和效果。

Deposition of d-gly-IgA in glomeruli is the characteristic of IgA nephropathy. However, the exact mechanism of d-gly-IgA induced pathological change is not clarified till now. Based on the recent studies and our preliminary study, it is speculated that the d-gly-IgA deposited in the glomeruli can stimulate mesangial cells activate TGF-β signaling pathway and secrete TNF-α, which will result in mesangial-podocyte cross talk and activate oxidative stress (ROS) reaction in podocyte. These reactions will cause apoptosis of podocyte in one hand, and also lead to expression of NLRP3, which in turn initiate podocyte-macrophage transdifferentiation (PMT). After PMT, podocyte could uptake more pathogenic IgA molecular and secrete large amount of inflammatory cytokines. All of these changes will result in fibrosis of renal tissue. However, STC1 could inhibit ROS activation and prevent further changes. Therefore, this study will be performed to clarify the mechanism of NLRP3/STC1 regulated IgA induced PMT. Results of this study will add further knowledge about the pathogenesis of IgAN and also provide information about effect of targeting NLRP3/STC1 as potential treatment of IgAN.