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

Abstract

BACKGROUND: 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.