Peroxidasin (PXDN) is a heme-peroxidase enzyme expressed in the extracellular matrix in several tissues. This enzyme catalyzes the formation of hypobromous acid (HOBr) from H2O2 and bromide. HOBr oxidizes amino acid residues to form covalent sulfilimine bonds in collagen IV in the basement membrane. This catalytic process displays a unique feature and was the first report of the presence of sulfilimine bond in a biological system. However, it is still unclear whether peroxidase activity of PXDN is restricted to sulfilimine-bond formation and whether other role than collagen IV exists. In this context, some investigations have been looking for other possible roles of PXDN. In fact, the aberrant PXDN expression has been associated with various cardiovascular disorders, cancer and, more recently, with kidney fibrosis. Dr. Bhave's group demonstrated in a renal fibrosis model that the loss of PXDN ameliorates fibrosis. In this situation, it would be odd for this to be due to the loss of collagen IV cross-links which one might think would make renal tubules more prone to injury. In addition, PXDN is found in the interstitial fibrosis co-localizing with fibronectin, suggesting fibroblasts as the cell of origin. Intriguingly, fibroblasts do not make much collagen IV. These evidences raise the question of whether PXDN might has a function beside of collagen IV cross-link formation in renal fibrosis. Given the central role played by fibroblasts in the development of fibrosis, the isolation of these cells for the in vitro study of the pathogenesis of the fibrosis is crucial. Therefore, we propose in this project to characterize PXDN in renal fibroblasts, looking at whether PXDN null fibroblasts behave differently from PXDN-containing fibroblasts in terms of TGF-beta signaling, which is involved in the fibrosis process, and matrix production. For this, we will use renal fibroblasts isolated from wildtype and PXDN knockout mice. Since kidney disease and hyperuricemia are strongly correlated, our future prospect following the finalization of this project is to look for these conditions in the presence of uric acid, since we already know that uric acid interacts with PXDN.
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