Pathology of Renal Matrix Metabolism

大多数肾脏疾病的肾功能特征性进行性下降与肾小球和间质纤维化的发展密切相关。间质纤维化的程度密切预测终末期肾病发展的最终临床结局。进行性间质纤维化可能由多种因素引发，包括免疫损伤、缺氧、肾质量减少和糖尿病;然而，这些损伤汇聚到与肾小管上皮细胞转分化为原肌成纤维细胞和成纤维细胞相关的最终共同途径，本实验室的重点是特定的基质金属蛋白酶的作用，在启动和延续的前，肾小管上皮细胞的纤维化转分化。具体而言，协调表达的两种基质金属蛋白酶，明胶酶A和MT 1-MMP，似乎在体外和体内驱动转分化过程。本提案的具体目的是在转录水平上定义，重点是TGF β、共同信号传导途径和连接明胶酶A和MT 1-MMP转录的转录因子。其次，将采用转基因方法来研究在TGF-β驱动的进行性肾纤维化模型中明胶酶A和MT 1-MMP基因表达之间的关系。最后，将使用转基因小鼠中的靶向条件表达来评估明胶酶A在体内直接诱导间质纤维化的能力。总之，这些互补的方法可以提供重要的进展性肾纤维化的机制的新见解，并指出特定的分子靶点，适合这些致残性疾病的新形式的治疗。

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.