Abstract: SA-OR071
The PAR-1 Antagonist Vorapaxar Ameliorates Kidney Injury and Tubulointerstitial Fibrosis in Experimental Obstructive Nephropathy
Session Information
- Mechanisms of Kidney and Cardiovascular Damage in CKD
November 09, 2019 | Location: 206, Walter E. Washington Convention Center
Abstract Time: 05:06 PM - 05:18 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Lok, Sarah W.Y., The University of Hong Kong, Hong Kong, China
- Yiu, Wai Han, The University of Hong Kong, Hong Kong, China
- Liu, Wing han, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
- Li, Hongyu, The University of Hong Kong, Hong Kong, China
- Xue, Rui, The University of Hong Kong, Hong Kong, China
- Chan, Loretta Y.Y., Queen Mary Hospital, Hong Kong, HONG KONG, China
- Leung, Joseph C K, The University of Hong Kong, Hong Kong, China
- Lai, Kar Neng, The University of Hong Kong, Hong Kong, China
- Tang, Sydney C.W., The University of Hong Kong, Hong Kong, China
Background
In addition to its role in tumor invasiveness and metastasis, protease-activated receptor-1 (PAR-1) has emerged as an inducer of kidney fibrosis. Whether it can be exploited as a therapeutic target remains unknown.
Methods
We assessed the effect of direct inhibition of PAR-1 on renal fibrosis by vorapaxar (a PAR-1 antagonist), a drug currently undergoing clinical trials for cardiovascular disease, in murine unilateral ureteral obstruction (UUO) model, and in cultured rat renal proximal tubular epithelial cells (NRK-52E). PAR-1 signaling was studied by real-time quantitative PCR, Western blotting and immunohistochemical staining.
Results
In UUO kidneys, PAR-1 and its activator, thrombin, were highly expressed in tubular cells. Mice treated with vorapaxar showed diminished renal fibrotic changes with attenuated fibronectin, α-smooth muscle actin and collagen expression versus control. Macrophage infiltration and ERK1/2 activation were also reduced in vorapaxar treated UUO kidneys. In NRK-52E cells, vorapaxar inhibited PAR-1 signaling, ameliorated thrombin-induced ERK1/2 activation and suppressed the downstream TGF-β signaling via both Smad-dependent and non-Smad-dependent MAPK signaling pathways.
Conclusion
Vorapaxar protects against kidney fibrosis in UUO model, partly via inhibition of thrombin/TGF-β/Smad signaling. This PAR-1 targeted therapeutic strategy may provide a novel treatment approach for chronic renal fibrotic diseases.
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.
Funding
- Government Support - Non-U.S.