The PAR-1 antagonist vorapaxar ameliorates kidney injury and tubulointerstitial fibrosis

• DOI: 10.1042/cs20200923
• Publication Date: 2020-10-20T11:52:03Z
• Authors: Sarah W.Y. Lok; Wai Han Yiu; Hongyu Li; Rui Xue; Yixin Zou; Bin Li; Kam Wa Chan; Loretta Y.Y. Chan; Joseph C.K. Leung; Kar Neng Lai; Sydney C.W. Tang
• Keywords: Inflammation; 0301 basic medicine; Extracellular Matrix Proteins; Mice, Inbred BALB C; Epithelial-Mesenchymal Transition; Pyridines; Macrophages; Endothelial Cells; Epithelial Cells; Kidney; Fibrosis; Cell Hypoxia; Rats; 3. Good health; Mice, Inbred C57BL; Lactones; Oxidative Stress; 03 medical and health sciences; Kidney Tubules; Animals; Extracellular Signal-Regulated MAP Kinases; Reactive Oxygen Species; Biomarkers

Abstract Protease-activated receptor (PAR)-1 has emerged as a key profibrotic player in various organs including kidney. PAR-1 activation leads to deposition of extracellular matrix (ECM) proteins the tubulointerstitium and induction epithelial–mesenchymal transition (EMT) during renal fibrosis. We tested anti-fibrotic potential vorapaxar, clinically approved antagonist for cardiovascular protection, an experimental kidney fibrosis model unilateral ureteral obstruction (UUO) AKI-to-chronic disease (CKD) ischemia–reperfusion injury (UIRI), dissected underlying renoprotective mechanisms using rat tubular epithelial cells. is activated mostly tubules both UUO UIRI models Vorapaxar significantly reduced ameliorated morphologic changes models. Amelioration was evident from down-regulation fibronectin (Fn), collagen α-smooth muscle actin (αSMA) injured Mechanistically, inhibition inhibited MAPK ERK1/2 transforming growth factor-β (TGF-β)-mediated Smad signaling, suppressed oxidative stress, overexpression pro-inflammatory cytokines macrophage infiltration into These beneficial effects were recapitulated cultured cells which vorapaxar thrombin- hypoxia-induced TGF-β expression ECM accumulation. In addition, mitigated capillary loss adhesion molecules on vascular endothelium AKI-to-CKD transition. The protects against UIRI. Its efficacy human CKD addition CV protection warrants further investigation.