Fibroblasts in Acute and Chronic Kidney Injury

描述(由申请人提供)： 成纤维细胞是肾脏结缔组织间隔(间质)的组成部分--就像在任何其他实质器官中一样。虽然肾脏中的成纤维细胞被一致认为是慢性纤维化的主要媒介，慢性肾功能衰竭的病理过程，但对肾脏成纤维细胞的生理作用知之甚少。我们的初步研究表明，成纤维细胞也是急性肾损伤自发修复的重要介质--这与它们在肾脏纤维化中的有害作用形成了鲜明对比。这就提出了以下问题：1)成纤维细胞如何促进急性肾损伤的修复？2)把“好”的成纤维细胞变成“坏的”成纤维细胞的分子机制是什么？虽然我们实验室的长期目标是阐明将有益的成纤维细胞转变为有害的成纤维细胞的分子机制开关，但本申请中提出的实验将阐明成纤维细胞如何促进急性肾损伤的修复，特别是FGF4在这一过程中的作用。在我们的初步研究中，我们对FACS分选的对照肾脏和缺血再灌注损伤后的肾脏成纤维细胞进行了全局基因表达谱分析，我们发现成纤维细胞生长因子4(FGF4)在急性损伤的成纤维细胞中特异表达，在正常肾脏中不表达(在纤维化肾脏中也不表达)。基于我们的初步研究，这一应用的中心假设是肾成纤维细胞在修复肾脏急性损伤中的有益作用依赖于FGF4。 公共卫生相关性：肾脏具有独特的修复急性损伤的能力。然而，肾脏的病理性修复，也就是所谓的“纤维化”，会破坏肾脏的结构，导致肾衰竭。这种纤维化的主要媒介是成纤维细胞。我们的初步研究表明，成纤维细胞是修复急性损伤所必需的，成纤维细胞在肾脏纤维化中是有害的。本申请中提出的实验旨在深入了解是什么使“好的”成纤维细胞变成了“坏的”成纤维细胞。

DESCRIPTION (provided by applicant): Fibroblasts are an integral constituent of the connective tissue compartment (the "interstitium") of the kidney - just like in any other parenchymal organ. While fibroblasts in the kidney are unanimously considered main mediators of chronic fibrogenesis, the pathological process that underlies chronic renal failure, little is known about the physiological role of renal fibroblasts. Our preliminary studies demonstrate that fibroblasts are also important mediators of spontaneous repair of acute kidney injury - in striking contrast to their detrimental role in kidney fibrosis. This raises the questions of 1) how fibroblasts contribute to repair of acute renal injury? and of 2) what the molecular mechanisms are that turn a "good" fibroblast into a "bad" fibroblast ? While the long-term goal of our laboratory is to elucidate the molecular mechanisms switch that turn beneficial fibroblasts into detrimental fibroblasts, experiments proposed in this application will elucidate how fibroblasts contribute to repair of acute renal injury, and specifically the role of FGF4 in this process. In our preliminary studies, we performed global gene expression profiling on FACS-sorted fibroblasts from control kidneys and kidneys after ischemia-reperfusion injury and we identified fibroblast growth factor 4 (FGF4) to be specifically expressed in fibroblasts in acute injury and not in normal kidney (and also not in fibrotic kidneys). Based on our preliminary studies, the central hypothesis of this application is that the beneficial role of renal fibroblasts in repair of acute injury in the kidney is dependent on FGF4. PUBLIC HEALTH RELEVANCE: The kidney possesses a unique capacity to repair itself from acute injury. However, pathological repair of the kidney, which is referred to as "fibrogenesis" destructs the kidney architecture and causes kidney failure. The main mediators of such fibrosis are fibroblasts. Our preliminary studies suggest that fibroblasts - which are detrimental in kidney fibrosis, are required for repair of acute injury. Experiments proposed in this application are designed to gain insights into what turns a "good" fibroblast into a "bad" fibroblast.