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

Canadian Institutes of Health Group on the Regulation of Vascular Contractility, Smooth Muscle Research Group, Departments of ¹Pharmacology and Therapeutics and ²Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1

Submitted 6 November 2002 ; accepted in final form 11 March 2003

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 PAR₁- and PAR₂-activating peptides (TFLLR-NH₂ and SLIGRL-NH₂) and proteinases (thrombin and trypsin) as PAR agonists in the isolated perfused rat kidney preparation. PAR₁ activation resulted in renal vasoconstriction and a marked reduction in the glomerular filtration rate (GFR). In contrast, PAR₂ 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 PAR₂-induced vasodilation was only partially blocked by N^G-nitro-L-arginine methyl ester, suggesting both nitric oxide-dependent and -independent mechanisms. Although PAR₄ mRNA was detected in renal parenchyma, the PAR₄-activating peptide AYPGKF-NH₂ had no effect on renal perfusion flow rate. We conclude that PAR₁ and PAR₂ play bidirectional roles in the regulation of renal hemodynamics.

nitric oxide; trypsin; thrombin; endothelium-derived relaxing factor; glomerular filtration rate

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