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Conference Paper: The PAR-1 Antagonist Vorapaxar Protects Against AKI To CKD Transition

TitleThe PAR-1 Antagonist Vorapaxar Protects Against AKI To CKD Transition
Authors
Issue Date2020
PublisherAmerican Society of Nephrology. The Journal's web site is located at http://www.jasn.org
Citation
American Society of Nephrology Annual Meeting: Kidney Week 2020: Reimagined, Virtual Meeting, 22-25 October 2020. In Journal of the American Society of Nephrology: Abstract Supplement, 2020, v. 31, p. 231, abstract PO0596 How to Cite?
AbstractBACKGROUND: Protease-activated receptor-1 (PAR-1) has been reported as a coagulation regulator in the pathophysiology of AKI. Beyond its normal function in haemostasis, aberrant PAR-1 signaling may lead to the development of tubulointersitial fibrosis, and subsequently CKD. METHODS: We investigated whether the administration of PAR-1 antagonist vorapaxar, an FDA-approved drug for reducing thrombotic cardiovascular events, has any renoprotective effect in a robust kidney fibrosis murine CKD model following unilateral ischemia reperfusion injury (UIRI), as well as in hypoxia-induced cultured rat proximal tubular epithelial cells (NRK-52E). RESULTS: Vorapaxar reduced morphological abnormalities and the expression of tubular injury marker KIM-1 in UIRI kidneys. Mice treated with vorapaxar showed less intrarenal accumulation of ECM proteins including fibronectin, α-smooth muscle actin and collagen 1 via TGF-β/Smad signaling after UIRI. IR-induced endothelial dysfunction and macrophage infiltration were also decreased by vorapaxar treatment. In NRK-52E cells, PAR-1 expression was activated under a hypoxic milieu associated with upregulation of TGF-β-induced ECM protein accumulation. CONCLUSION: Vorapaxar diminishes renal fibrosis through TGF-β/Smad signaling in UIRI model, and protects against tubular injury during AKI to CKD transition. A PAR-1 targeted strategy by vorapaxar as a therapeutic approach in human CKD warrants further. Funding: Health and Medical Research Fund (HMRF) of Hong Kong (grant no. 05163596), Research Grants Council of Hong Kong (Collaborative Research Fund, grant no. C7018-16G), and Hong Kong Society of Nephrology/HK Kidney Foundation Research Grant 2018.
DescriptionSesson: CKD Mechanisms 1 - Abstract Poster: PO0596
Persistent Identifierhttp://hdl.handle.net/10722/307966
ISSN
2023 Impact Factor: 10.3
2023 SCImago Journal Rankings: 3.409

 

DC FieldValueLanguage
dc.contributor.authorLOK, WY-
dc.contributor.authorYiu, WH-
dc.contributor.authorChan, LYY-
dc.contributor.authorLeung, JCK-
dc.contributor.authorLai, KN-
dc.contributor.authorTang, SCW-
dc.date.accessioned2021-11-12T13:40:30Z-
dc.date.available2021-11-12T13:40:30Z-
dc.date.issued2020-
dc.identifier.citationAmerican Society of Nephrology Annual Meeting: Kidney Week 2020: Reimagined, Virtual Meeting, 22-25 October 2020. In Journal of the American Society of Nephrology: Abstract Supplement, 2020, v. 31, p. 231, abstract PO0596-
dc.identifier.issn1046-6673-
dc.identifier.urihttp://hdl.handle.net/10722/307966-
dc.descriptionSesson: CKD Mechanisms 1 - Abstract Poster: PO0596-
dc.description.abstractBACKGROUND: Protease-activated receptor-1 (PAR-1) has been reported as a coagulation regulator in the pathophysiology of AKI. Beyond its normal function in haemostasis, aberrant PAR-1 signaling may lead to the development of tubulointersitial fibrosis, and subsequently CKD. METHODS: We investigated whether the administration of PAR-1 antagonist vorapaxar, an FDA-approved drug for reducing thrombotic cardiovascular events, has any renoprotective effect in a robust kidney fibrosis murine CKD model following unilateral ischemia reperfusion injury (UIRI), as well as in hypoxia-induced cultured rat proximal tubular epithelial cells (NRK-52E). RESULTS: Vorapaxar reduced morphological abnormalities and the expression of tubular injury marker KIM-1 in UIRI kidneys. Mice treated with vorapaxar showed less intrarenal accumulation of ECM proteins including fibronectin, α-smooth muscle actin and collagen 1 via TGF-β/Smad signaling after UIRI. IR-induced endothelial dysfunction and macrophage infiltration were also decreased by vorapaxar treatment. In NRK-52E cells, PAR-1 expression was activated under a hypoxic milieu associated with upregulation of TGF-β-induced ECM protein accumulation. CONCLUSION: Vorapaxar diminishes renal fibrosis through TGF-β/Smad signaling in UIRI model, and protects against tubular injury during AKI to CKD transition. A PAR-1 targeted strategy by vorapaxar as a therapeutic approach in human CKD warrants further. Funding: Health and Medical Research Fund (HMRF) of Hong Kong (grant no. 05163596), Research Grants Council of Hong Kong (Collaborative Research Fund, grant no. C7018-16G), and Hong Kong Society of Nephrology/HK Kidney Foundation Research Grant 2018.-
dc.languageeng-
dc.publisherAmerican Society of Nephrology. The Journal's web site is located at http://www.jasn.org-
dc.relation.ispartofJournal of the American Society of Nephrology-
dc.relation.ispartofAmerican Society of Nephrology Annual Meeting: Kidney Week 2020-
dc.titleThe PAR-1 Antagonist Vorapaxar Protects Against AKI To CKD Transition-
dc.typeConference_Paper-
dc.identifier.emailYiu, WH: whyiu@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.natureabstract-
dc.identifier.hkuros329902-
dc.identifier.volume31-
dc.identifier.issueSuppl.-
dc.identifier.spage231, abstract PO0596-
dc.identifier.epage231, abstract PO0596-
dc.publisher.placeUnited States-

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