Physiological roles and pathological involvement of protease activated receptors in renal diseases: Therapeutic advances and challenges

Studies have demonstrated that protease activated receptors (PARs) with four subtypes (PAR1-4) are mainly expressed in the renal epithelial, endothelial and podocyte cells. Evidently, the PAR-1 and PAR-2 have shown differential therapeutic outcomes in rodent models of type-1 and type-2 diabetic kidney diseases due to distinct etiological basis of each disease type. Both PAR-1 and PAR-2 blockers/knock-out have abolished the drug-induced nephrotoxicity in rodents by suppression of tubular inflammation and fibrosis. Notably, PAR-2 inhibition was found to improve autophagy in the urethral obstruction model. Only the PAR-1/4 subtypes have emerged as a therapeutic target for the treatment of experimentally induced nephrotic syndrome where their respective antibodies attenuated the podocyte apoptosis. So far the PAR-2/PAR-4 subtypes involvement has been tested in sepsis acute kidney injury and renal ischemia-reperfusion model. This review discusses the existing gaps, therapeutic advances and future perspectives related to the roles of different PARs in kidney diseases.