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Kidney Week

Abstract: PO0596

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

Session Information

  • CKD Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Lok, Sarah W.Y., The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
  • Yiu, Wai Han, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
  • Chan, Loretta Y.Y., The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
  • Leung, Joseph C K, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
  • Lai, Kar Neng, The University of Hong Kong, Hong Kong, Hong Kong
  • Tang, Sydney C.W., The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
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.