Alport综合征是一种遗传性进行性肾炎，男性X连锁显性遗传的患者40岁前发生终末期肾脏病的比例高达90%。足细胞损伤、蛋白尿进行性加重与Alport综合征疾病进展密切相关。研究发现敲除USAG-1的Alport综合征小鼠蛋白尿减轻、肾小球硬化比例减少，但USAG-1是否通过足细胞发挥作用及可能的机制远未澄清。本研究应用USAG-1抗体干预Alport综合征小鼠，检测疾病不同阶段USAG-1的表达与足细胞损伤的关系，证明USAG-1在Alport综合征中对足细胞的损伤作用；体外培养足细胞，通过过表达USAG-1、用USAG-1重组蛋白处理足细胞，检测Wnt信号通路关键分子，应用Wnt信号通路特异性抑制剂，进一步检测足细胞损伤指标，揭示USAG-1导致足细胞损伤的分子机制。本课题将从新的角度加深对Alport综合征疾病进展机制的理解，为寻求新的治疗靶点提供重要理论依据。

Alport syndrome is a hereditary renal disease, characterized by hematuria, proteinuria, and progressing renal failure. Males with X linked Alport syndrome progress inevitably to ESRD, with ESRD risks of 90% by age 40. It has been shown that podocyte injury was involved in Alport syndrome. Recently, USAG-1 (uterine sensitization–associated gene-1) has been proved to be an important factor in the progressing of Alport syndrome. Ablation of Usag1 in Col4a3–/– mice led to normalization of glomerular basement membrane (GBM) ultrastructure, less albuminuria and preserved renal function. We hypothesized that USAG-1 contributes to podocyte injury via activation of Wnt signaling pathway in Alport syndrome. Col4a3–/– mice was treated with a neutralizing antibody against USAG-1. Electron microscopy was used to identify podocyte injury and immunohistochemistry was used to identify the distribution of USAG-1. Real time PCR and western blot was used to detect the expression of nephrin, synaptopodin, USAG-1 andβ-catenin. Furthermore, the activation of Wnt signaling and podocyte injury was detected by overexpression of USAG-1 or adding recombinant USAG1 in cultured podocytes in vitro. Podocyte injury was detected by blocking Wnt signaling with Dickkopf-1 (Dkk1) or Wnt inhibitory factor-1 (WIF-1). This study may provide a new insight in mechanism of disease progression for Alport syndrome. USAG-1 may sever as a new potential theraputic target for the treatment of Alport syndrome in future.