Role of protease activated receptor 4 (PAR4) in mouse models of acute and chronic kidney injury.

Protease activated receptor 4 (PAR4) is a GPCR activated by thrombin. It not only contributes most of the platelet-derived thrombin, but also procoagulant microparticle formation, increased fibrin deposition, and initiation of platelet-stimulated inflammation. In addition, PAR4 is expressed on other cell types including endothelial cells. Under inflammatory conditions, PAR4 is overexpressed via epigenetic demethylation of the PAR4 gene, F2RL3 . PAR4 knockout studies have determined a role for PAR4 in ischemia reperfusion injury in brain and PAR4 KO mice display normal cardiac function but present less myocyte death and cardiac dysfunction in response to acute myocardial infarction. While PAR4 has been reported to be expressed within the kidney, the contribution of PAR4 to acute kidney injury (AKI) and chronic kidney disease (CKD) is not well understood. Here we report that PAR4 KO mice are protected against kidney injury in two mouse models. First, PAR4 KO mice are protected against induction of markers of both fibrosis and inflammation in two different models of kidney injury: 1) seven days following unilateral ureter obstruction (UUO) 2) an AKI-CKD model of ischemia reperfusion followed eight days by contralateral nephrectomy. We further show that PAR4 expression in the kidney is low in control mouse kidney but induced over time following UUO. PAR4 KO mice are protected against blood urea nitrogen (BUN) and glomerular filtration rate (GFR) kidney function pathologies in the AKI-CKD model.