Bidirectional regulation of renal hemodynamics by activation of PAR1 and PAR2 in isolated perfused rat kidney

Proteinase-activated receptors (PARs) are activated by either serine proteinases or synthetic peptides corresponding to the NH2-terminal tethered ligand sequences that are unmasked by proteolytic cleavage. Although PARs are highly expressed in the kidney, their roles in regulating renal function are not known. In the present study, we evaluated the impact of PAR activation on renal hemodynamics using PAR(1)- and PAR(2)-activating peptides (TFLLR-NH2 and SLIGRL-NH2) and proteinases ( thrombin and trypsin) as PAR agonists in the isolated perfused rat kidney preparation. PAR(1) activation resulted in renal vasoconstriction and a marked reduction in the glomerular filtration rate (GFR). In contrast, PAR(2) activation caused vasodilation, partially reversing the vasoconstriction induced by TFLLR-NH2 and ANG II and increasing GFR that had been prereduced by ANG II. The vasoconstrictor actions of PAR1 activation were abolished by protein kinase C inhibition. The PAR(2)-induced vasodilation was only partially blocked by N-G-nitro-L-arginine methyl ester, suggesting both nitric oxide-dependent and - independent mechanisms. Although PAR(4) mRNA was detected in renal parenchyma, the PAR(4)-activating peptide AYPGKF-NH2 had no effect on renal perfusion flow rate. We conclude that PAR(1) and PAR(2) play bidirectional roles in the regulation of renal hemodynamics.