Tubulovascular protection from protease-activated receptor-1 depletion during AKI-to-CKD transition

Abstract

Background Thromboembolic events are prevalent in chronic kidney disease (CKD) patients due to increased thrombin generation leading to a hypercoagulable state. We previously demonstrated that inhibition of protease-activated receptor-1 (PAR-1) by vorapaxar reduces kidney fibrosis. Methods We used an animal model of unilateral ischemia-reperfusion (UIRI)-induced CKD to explore the tubulovascular crosstalk mechanisms of PAR-1 in AKI-to-CKD transition. Results During the early phase of AKI, PAR-1 deficient mice exhibited reduced kidney inflammation, vascular injury and preserved endothelial integrity and capillary permeability. During the transition phase to CKD, PAR-1 deficiency preserved kidney function and diminished tubulointerstitial fibrosis via downregulated TGF-β/Smad signaling. Maladaptive repair in the microvasculature after AKI further exacerbated focal hypoxia with capillary rarefaction, which was rescued by stabilization of HIF and increased tubular VEGFA in PAR-1 deficient mice. Chronic inflammation was also prevented with reduced kidney infiltration by both M1- and M2- polarized macrophages. In thrombin-induced human dermal microvascular endothelial cells (HDMECs), PAR-1 mediated vascular injury through activation of NFκB and ERK MAPK pathways. Gene silencing of PAR-1 exerted microvascular protection via a tubulovascular crosstalk mechanism during hypoxia in HDMECs. Finally, pharmacologic blockade of PAR-1 with vorapaxar improved kidney morphology, promoted vascular regenerative capacity, and reduced inflammation and fibrosis depending on the time of initiation. 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.

Stage lighting on PAR-1: a step further in the understanding of acquired focal and segmental glomerulosclerosis

“…Likewise, PAR-1 inhibition has been suggested as kidney protective in pathophysiological settings. Indeed, a very recent publication shows that PAR-1 invalidation protects against the transition to chronic kidney disease in a mouse ischemia-reperfusion model 5 .…”