Fibroblasts in Acute and Chronic Kidney Injury

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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.