Tubulovascular Protection of Protease-Activated Receptor-1 Deficiency During AKI-to-CKD Transition

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Background: Thromboembolic event is evident in CKD patients with high risk of cardiovascular disease due to aberrant activation of the coagulation system. Endothelial cell injury leading to renal microvascular damage and rarefaction is a prominent feature in CKD. Our previous study demonstrates that protease-activated receptor-1 (PAR-1) inhibition by a clinically approved antagonist vorapaxar mitigates kidney fibrosis. However, its role in vascular damage following AKI contributing to CKD progression remains unexplored. Methods: We employed the animal model of unilateral ischemia reperfusion (UIRI)-induced CKD to explore tubulovascular crosstalk of PAR-1 in AKI-to-CKD transition using transgenic PAR-1 deficient mice and vorapaxar treatment at different disease stages. Evans blue vascular permeability assay was performed to assess endothelial injury at both AKI and CKD stages. Results: During AKI, mice with PAR-1 deficiency exhibited reduced renal inflammation, vascular injury and preserved capillary permeability. PAR-1 deficiency preserved kidney function and diminished tubulointerstitial fibrosis via TGF-β/Smad during transition phase to CKD. Maladaptive repair in the microvasculature after AKI exacerbated focal hypoxia with capillary rarefaction, which was rescued by Akt/GSK-3β-regulated stabilization of HIF and increase in VEGF in PAR-1 deficient mice. Chronic inflammation was prevented in PAR-1 deficient mice with reduced recruitment of infiltrating macrophages, and both M1- and M2- polarized macrophages. Finally, vorapaxar post-treatment after UIRI exerted greatest anti-fibrotic effect with alleviated ECM proteins and TGF-β1. Importantly, vascular regenerative capacity was higher in mice treated with vorapaxar during AKI, particularly showing significant increase of VEGF in full treatment and VEGFR2 in pre-treatment with vorapaxar. Conclusions: Our findings elucidate a detrimental role of PAR-1 in vascular dysfunction and profibrotic responses upon tissue injury during AKI-to-CKD transition and provide an attractive therapeutic strategy for post-injury repair in AKI. Funding: Health and Medical Research Fund (HMRF) of Hong Kong (grant no. 05163596), Research Grants Council of Hong Kong (General Research Fund, grant no. 17118720), the Mr & Mrs Tam Wing Fan Edmund Renal Research Fund and HKSN/HK Kidney Foundation Research Grant 2018.

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