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

Clin Sci (Lond). 2020 Nov 13;134(21):2873-2891. doi: 10.1042/CS20200923.

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

Keywords: PAR-1; chronic kidney disease; renal fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cell Hypoxia / drug effects
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Epithelial-Mesenchymal Transition / drug effects
  • Extracellular Matrix Proteins / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibrosis
  • Inflammation / pathology
  • Kidney / drug effects
  • Kidney / injuries*
  • Kidney / pathology
  • Kidney Tubules / drug effects
  • Kidney Tubules / pathology
  • Lactones / pharmacology*
  • Macrophages / drug effects
  • Macrophages / pathology
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Oxidative Stress / drug effects
  • Pyridines / pharmacology*
  • Rats
  • Reactive Oxygen Species / metabolism
  • Receptor, PAR-1 / antagonists & inhibitors*
  • Receptor, PAR-1 / metabolism
  • Reperfusion Injury / complications
  • Smad3 Protein / metabolism
  • Thrombin / pharmacology
  • Transforming Growth Factor beta / metabolism
  • Up-Regulation / drug effects
  • Ureteral Obstruction / complications
  • Ureteral Obstruction / pathology

Substances

  • Biomarkers
  • Extracellular Matrix Proteins
  • Lactones
  • Pyridines
  • Reactive Oxygen Species
  • Receptor, PAR-1
  • Smad3 Protein
  • Transforming Growth Factor beta
  • Extracellular Signal-Regulated MAP Kinases
  • Thrombin
  • vorapaxar