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Article: The PAR-1 antagonist Vorapaxar ameliorates kidney injury and tubulointerstitial fibrosis

TitleThe PAR-1 antagonist Vorapaxar ameliorates kidney injury and tubulointerstitial fibrosis
Authors
KeywordsChronic kidney disease
PAR-1
Renal fibrosis
Issue Date2020
PublisherPortland Press Ltd. The Journal's web site is located at http://www.clinsci.org/
Citation
Clinical Science, 2020, v. 134 n. 21, p. 2873-2891 How to Cite?
AbstractProtease-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.
Persistent Identifierhttp://hdl.handle.net/10722/293683
ISSN
2023 Impact Factor: 6.7
2023 SCImago Journal Rankings: 1.565
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLok, SWY-
dc.contributor.authorYiu, WH-
dc.contributor.authorLi, H-
dc.contributor.authorXue, R-
dc.contributor.authorZou, Y-
dc.contributor.authorLi, B-
dc.contributor.authorChan, KW-
dc.contributor.authorChan, LYY-
dc.contributor.authorLeung, JCK-
dc.contributor.authorLai, KN-
dc.contributor.authorTang, SCW-
dc.date.accessioned2020-11-23T08:20:18Z-
dc.date.available2020-11-23T08:20:18Z-
dc.date.issued2020-
dc.identifier.citationClinical Science, 2020, v. 134 n. 21, p. 2873-2891-
dc.identifier.issn0143-5221-
dc.identifier.urihttp://hdl.handle.net/10722/293683-
dc.description.abstractProtease-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.-
dc.languageeng-
dc.publisherPortland Press Ltd. The Journal's web site is located at http://www.clinsci.org/-
dc.relation.ispartofClinical Science-
dc.rightsThe final version of record is available at http://www.clinsci.org/-
dc.subjectChronic kidney disease-
dc.subjectPAR-1-
dc.subjectRenal fibrosis-
dc.titleThe PAR-1 antagonist Vorapaxar ameliorates kidney injury and tubulointerstitial fibrosis-
dc.typeArticle-
dc.identifier.emailYiu, WH: whyiu@hku.hk-
dc.identifier.emailChan, KW: chriskwc@hku.hk-
dc.identifier.emailChan, LYY: yychanb@hku.hk-
dc.identifier.emailLeung, JCK: jckleung@hku.hk-
dc.identifier.emailLai, KN: knlai@hku.hk-
dc.identifier.emailTang, SCW: scwtang@hku.hk-
dc.identifier.authorityLeung, JCK=rp00448-
dc.identifier.authorityLai, KN=rp00324-
dc.identifier.authorityTang, SCW=rp00480-
dc.description.naturepostprint-
dc.identifier.doi10.1042/CS20200923-
dc.identifier.pmid33078834-
dc.identifier.scopuseid_2-s2.0-85096202896-
dc.identifier.hkuros318917-
dc.identifier.volume134-
dc.identifier.issue21-
dc.identifier.spage2873-
dc.identifier.epage2891-
dc.identifier.isiWOS:000592321600001-
dc.publisher.placeUnited Kingdom-

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