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Title: Pathogenesis of Renal Fibrosis: a Role for Proteinase-activated Receptor-2
Author: Chung, Hyun Jae
Advisor: Hollenberg, Morley
Muruve, Daniel
Keywords: Pathology
Issue Date: 28-Jan-2013
Abstract: Renal fibrosis is the final manifestation of all progressive chronic kidney disease with a significant morbidity and mortality. However, the underlying mechanisms remain largely unknown. Proteinase-activated Receptor-2 (PAR2) is a G-protein-coupled receptor that is proteolytically activated by serine proteinases such as trypsin. In our in vitro studies, we found that stimulation of PAR2 in human proximal tubular cells with PAR2-activating peptide alone significantly upregulated expression of CCN2 and did so synergistically to augment Transforming growth factor-β (TGF-β)-induced CCN2 production. This synergy was reduced by MAPKinase inhibition. We also found that PAR2 deficiency in mice with unilateral ureteral obstruction (UUO) significantly reduced tubular injuries and fibrosis, and synthesis of renal collagen and α-smooth muscle actin at 7 days post UUO. Our findings demonstrate the potential contribution of PAR2 to renal injury and fibrosis at an early time point due to the ability of PAR2 to augment the production of a profibrotic cytokine.
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