膜性肾病（MN）是成人肾病综合症最常见的病因之一。补体膜攻击复合物（MAC）所致的足细胞损伤是MN发病机制的核心环节，但其下游关键信号通路和独立于MAC之外的足细胞损伤机制仍不清楚。我们前期MN肾小球全转录组学研究显示MN患者肾小球NRIP2的mRNA表达显著高于正常肾小球，而且权重基因共表达网络分析（WGCNA）发现NRIP2在MN足细胞损伤调控网络中处于最核心的环节。我们在独立样本中证实MN患者肾小球NRIP2的mRNA和蛋白均显著高于正常肾小球，更为重要的是我们还发现NRIP2在肾脏高度特异性的分布于肾小球的足细胞。另一方面，维甲酸信号通路是肾脏发育、足细胞分化存活损伤的关键信号通路之一，而既往研究显示NRIP2能与配体活化的RARα维甲酸受体结合。因此，我们推测NRIP2可能通过调控维甲酸信号通路，继而在MN足细胞损伤中发挥重要作用。本研究拟通过体外足细胞和动物模型验证这一假说。

Membranous nephropathy (MN) is the most common cause of the nephrotic syndrome in adults. Complement activation and formation of the membrane attack complex (MAC), which is triggered by immune complex deposition, have major roles in podocyte injury and proteinuria, however, the downstream signal of MAC and podocyte injury mechanisms independent of MAC remains elusive. Our previous study on transcriptome expression profile of glomeruli in patients with MN showed that expression of NRIP2 (nuclear receptor interacting protein 2) mRNA in MN glomeruli were significantly higher than normal controls, and WGCNA, the weighted gene co-expression network analysis, identified NRIP2 as the most centralized intramodular hub gene, suggesting the NRIP2 could be important in the pathogenesis of MN. These findings were confirmed in an independent group of patient and normal controls by qPCR and IHC method. Moreover, we found that NRIP2 is specifically located in podocyte in kidney. In addition, the previous studies showed that NRIP2 interacts with RARα (retinoic acid receptor, alpha) in retinoid acid (RA) signal pathway, which is critical in kidney development, podocyte differentiation and regenergation and is also associated with podocyte injury in various kidney disease. NRIP2 can bind to the RARα in the existence of RAR ligand. Therefore, we hypothesize that NRIP2 could have an important role in podocyte injury in patients with MN though the regulation of RA signal pathway. In this project, we will prove this hypothesis in vitro and in vivo.