Pathology of Renal Matrix Metabolism

肾功能的进行性下降是大多数肾脏疾病的特征，与肾小球和间质纤维化的发展密切相关。间质纤维化的程度与终末期肾病的发展密切相关，可以预测最终的临床结果。进行性间质纤维化可能由多种因素引起，包括免疫损伤、低氧、肾质量减少和糖尿病；然而，这些因素汇聚到与肾小管上皮细胞转分化相关的最终共同途径，即促硬化的肌成纤维细胞和成纤维细胞。本实验室重点研究了特定的基质金属蛋白酶在肾小管上皮细胞促纤维化转分化的启动和持续中的作用。具体地说，在体外和体内，明胶酶A和MT1-MMP这两种基质金属蛋白酶的协同表达似乎推动了转分化过程。这一建议的具体目的是在转录水平上定义，重点是TGFβ，连接明胶酶A和MT1-MMP转录的常见信号通路和转录因子。其次，将采用转基因方法来研究在转化生长因子-β驱动的进行性肾纤维化模型中明胶酶A和MT1-基质金属蛋白酶基因表达之间的关系。最后，明胶酶A在体内直接诱导间质纤维化的能力将在转基因小鼠中使用靶向条件表达进行评估。综上所述，这些互补的方法可能为进行性肾纤维化的机制提供重要的新见解，并指出适合于这些致残性疾病的新形式治疗的特定分子靶点。

The progressive decline in renal function characteristic of most forms of renal disease is intimately associated with the development of glomerular and interstitial fibrosis. The extent of interstitial fibrosis closely predicts the ultimate clinical outcome in terms of development of end stage renal disease. Progressive interstitial fibrosis may be initiated by multiple factors, including immune injury, hypoxia, reduction in renal mass and diabetes mellitus; however, these insults converge to a final common pathway associated with tubular epithelial cell transdifferentiation to pro- sclerotic myofibroblasts and fibroblasts, This laboratory has focused on the role of specific matrix metalloproteinases in the initiation and perpetuation of the pro-fibrotic transdifferentiation of tubular epithelial cells. Specifically, coordinate expression of two matrix metalloproteinases, gelatinase A and MT1-MMP, appears to drive the transdifferentiation process in vitro and in vivo. The Specific Aims of this proposal are to define at the transcriptional level, with an emphasis on TGFbeta, common signaling pathways and transcription factors which link gelatinase A and MT1-MMP transcription. Secondly, a transgenic approach will be taken to examine the relationship between gelatinase A and MT1-MMP gene expression in a TGF-beta-driven model of progressive renal fibrosis. Finally, the ability of gelatinase A to directly induce interstitial fibrosis in vivo will be assessed using targeted conditional expression in the transgenic mouse. Taken together, these complementary approaches may provide important new insights into the mechanisms of progressive renal fibrosis and point out specific molecular targets suitable for new forms of therapies of these disabling disorders.