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隔室（“结缔组织”）的组成部分-就像任何其他实质器官一样。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介质，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-与其在肾纤维化中的有害作用形成鲜明对比。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？以及2）是什么分子机制将“好的”成纤维细胞变成“坏的”成纤维细胞？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化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有助于急性肾损伤的修复，特别是FGF 4在此过程中的作用。在我们的初步研究中，我们对来自对照肾脏和缺血再灌注损伤后肾脏的FACS分选的成纤维细胞进行了全局基因表达谱分析，并且我们鉴定了成纤维细胞生长因子4（FGF 4）在急性损伤中的成纤维细胞中特异性表达，而在正常肾脏中不表达（也不在纤维化肾脏中）。根据我们的初步研究，该应用的中心假设是肾成纤维细胞在肾脏急性损伤修复中的有益作用依赖于FGF 4。 公共卫生相关性：肾脏具有从急性损伤中自我修复的独特能力。然而，肾脏的病理性修复（其被称为“纤维形成”）破坏肾脏结构并导致肾衰竭。这种纤维化的主要介质是成纤维细胞。我们的初步研究表明，成纤维细胞-这是有害的肾纤维化，是需要修复急性损伤。本申请中提出的实验旨在深入了解是什么将“好”成纤维细胞变成“坏”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.