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

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-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 downregulation of fibronectin, collagen and α-smooth muscle actin in the injured kidney. Mechanistically, inhibition of PAR-1 inhibited MAPK ERK1/2 and 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.

Effects of secretome derived from macrophages exposed to calcium oxalate crystals on renal fibroblast activation

“…The excessive accumulation of ECM is another important feature of tissue or renal fibrosis. Several previous studies have reported the increases of main ECM components, including collagens, fibronectin and proteoglycans in renal interstitial fibrotic tissues 76 , 77 . In addition, in vitro studies have demonstrated that α-SMA-expressing renal fibroblasts promote the synthesis of ECM components, including collagen type I and fibronectin 65 , 78 .…”

KLK8 promotes the proliferation and metastasis of colorectal cancer via the activation of EMT associated with PAR1

“…The EMT process is controlled by a network of signalling pathways such as transforming growth factor (TGF)-β/Smad and Hippo pathways, and is executed by a subset of transcription factors including ZEB1/2, Snail/Slug, Twist, and YAP/TAZ [ 28 , 61 , 64 – 69 ]. Previous studies have reported that PAR-1 activation contributes to renal EMT and interstitial fibrosis during chronic obstructive nephropathy [ 70 , 71 ]. Pharmacological inhibition of PAR-1 provides a renoprotective strategy by virtue of its anti-fibrotic effects, mediated partly via inhibition of Smad-dependent TGF-β signalling [ 71 ].…”

“…Previous studies have reported that PAR-1 activation contributes to renal EMT and interstitial fibrosis during chronic obstructive nephropathy [ 70 , 71 ]. Pharmacological inhibition of PAR-1 provides a renoprotective strategy by virtue of its anti-fibrotic effects, mediated partly via inhibition of Smad-dependent TGF-β signalling [ 71 ]. In gastric and CRC cells, PAR-1 activation leads to upregulation of pro-EMT transcriptional factor Snail and Twist, respectively [ 28 , 67 ].…”

Identification of circular RNA expression profiles in renal fibrosis induced by obstructive injury

“…The miR-466i and miR-466k are sponged by circRNA-Kcnq1ot1 participate in cardiomyocytes apoptosis in acute myocardial infarction [ 29 ]. By analyzing the ceRNA results, we reveal that the up-regulated circRNA-3109 or circRNA-14838 is able to suppress miR-615-5p, which binds to collagen I, may promote renal fibrosis [ 30 ]. Furthermore, it is reasonable to assume that the dysregulated circRNA-2862 may sponge with miRNA-709, circRNA-6671 with miRNA-3473, circRNA-6471 with miRNA-466 and relieve their suppression to downstream target may participate in the process of kidney injured by UUO.…”