Gui Yu, Loutzenhiser Rodger, Hollenberg Morley D
Canadian Institutes of Health Group on the Regulation of Vascular Contractility, Smooth Muscle Research Group, Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Am J Physiol Renal Physiol. 2003 Jul;285(1):F95-104. doi: 10.1152/ajprenal.00396.2002. Epub 2003 Mar 18.
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 NG-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.
蛋白酶激活受体（PARs）可被丝氨酸蛋白酶或与经蛋白水解切割后暴露的氨基末端拴系配体序列相对应的合成肽激活。尽管PARs在肾脏中高度表达，但其在调节肾功能中的作用尚不清楚。在本研究中，我们在离体灌注大鼠肾脏制备中，使用PAR1和PAR2激活肽（TFLLR-NH2和SLIGRL-NH2）以及蛋白酶（凝血酶和胰蛋白酶）作为PAR激动剂，评估了PAR激活对肾血流动力学的影响。PAR1激活导致肾血管收缩和肾小球滤过率（GFR）显著降低。相反，PAR2激活引起血管舒张，部分逆转了TFLLR-NH2和血管紧张素II（ANG II）诱导的血管收缩，并增加了已被ANG II预先降低的GFR。蛋白激酶C抑制可消除PAR1激活的血管收缩作用。PAR2诱导的血管舒张仅被NG-硝基-L-精氨酸甲酯部分阻断，提示存在一氧化氮依赖性和非依赖性机制。尽管在肾实质中检测到PAR4 mRNA，但PAR4激活肽AYPGKF-NH2对肾灌注流速没有影响。我们得出结论，PAR1和PAR2在肾血流动力学调节中发挥双向作用。
