title: Proteinase-activated receptors 1 and 2 exert opposite effects on renal renin release.
abstract: Proteinase-activated receptors (PARs) 1 to 4 are highly expressed in the kidney and are involved in the regulation of renal hemodynamics and tubular function. Since intravascular infusion of the proteinase thrombin, which activates PARs, has been shown to decrease plasma renin activity in rats, we investigated the effects of the respective PAR subtypes on renin release using the isolated perfused mouse kidney model. Thrombin dose-dependently reduced perfusate flow and inhibited renin secretion rates (RSRs) that had been prestimulated by the β-adrenoreceptor agonist isoproterenol. The suppression of RSRs was prevented by the selective PAR1 inhibitor SCH79797, and direct activation of PAR1 by TFLLR mimicked the effects of thrombin on RSRs and vascular tone. Moreover, TFLLR suppressed the stimulations of RSRs in response to the loop diuretic bumetanide, to prostaglandin E(2), or to a decrease in renal perfusion pressure but not in response to a reduction in extracellular calcium. The PAR2-activating peptide SLIGRL concentration dependently increased RSR and perfusate flow. The stimulation of RSRs by SLIGRL was markedly attenuated by N(G)-nitro-L-arginine methyl ester, suggesting an NO-dependent mechanism. Activation of PAR4 by AYPGKF did not modulate RSRs or perfusate flow. PAR1 and PAR2 immunoreactivity were detected in the juxtaglomerular region and were colocalized with renin immunoreactivity. Our data provide evidence that PAR1 activation inhibits renal renin secretion and induces renal vasoconstriction, whereas PAR2 activation stimulates renin release and induces vasodilation mainly via the release of NO.
authors.affiliation: Institute of Physiology, University of Regensburg, Regensburg, Germany. klaus.hoecherl@chemie.uni-regensburg.de
authors.forename: Klaus
authors.initials: K
authors.lastname: Höcherl
authors.forename: Melanie
authors.initials: M
authors.lastname: Gerl
authors.forename: Frank
authors.initials: F
authors.lastname: Schweda
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007545:Isoproterenol / Q000494:pharmacology; D007606:Juxtaglomerular Apparatus / Q000187:drug effects / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000187:drug effects / Q000378:metabolism*; D044464:Receptor, PAR-2 / Q000187:drug effects / Q000378:metabolism*; D012083:Renin / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors
chemical_list: D000318:Adrenergic beta-Agonists; C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D009842:Oligopeptides; D011758:Pyrroles; D011799:Quinazolines; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; D009569:Nitric Oxide; D013917:Thrombin; D012083:Renin; D007545:Isoproterenol; D010975:Platelet Aggregation Inhibitors