Abstract P160: Dual-Specificity Protein Phosphatase 5 Regulates Renal Vessel Myogenic Response via Direct Modulating Extracellular Signal-Related Kinase and Protein Kinase C

Abstract

Dual-specificity protein phosphatase 5 (DUSP5) is a serine-threonine phosphatase that regulates intracellular signal transduction by dephosphorylating extracellular signal-related kinase (ERK1/2) and protein kinase C (PKC). We previously reported that knockout (KO) of Dusp5 enhanced the myogenic response and autoregulation of cerebral and renal circulation in association with increased levels of phosphorylated ERK1/2 (p-ERK1/2) and phosphorylated protein kinase C (p-PKC) in the vessels. However, the influence of increased levels of p-ERK1/2 and p-PKC on vascular function is unknown. This study investigated whether Dusp5 regulates myogenic reactivity of freshly isolated middle cerebral arteries (MCA, ~140 um), cerebral penetrating arteries (PA, ~15 um), renal arcuate arterioles (AA, ~ 50 um), and interlobular arterioles (IA, ~25 um) of Dusp5 KO and WT rats via inhibition of ERK1/2 and PKC. The myogenic reactivity of both cerebral and renal vasculature was compared at different perfusion pressure. The inner diameters of IA and AA decreased to 87.24 ± 0.76 % and 92.81 ± 2.90 %, respectively, in Dusp5 KO rats (n=4), but only to 99.70 ± 2.76 % and 98.85 ± 2.79 %, respectively, in WT rats (n=4) when perfusion pressure was increased from 60 to 180 mmHg. Similar results were found in MCA and PA. Inhibition of ERK1/2 with FR 180204 (1 uM) or PKC with BIM III (300 nM) diminished myogenic reactivity to a greater extent in cerebral and renal vessels of Dusp5 KO versus WT rats. These results indicate that downregulation of DUSP5 expression increases the myogenic reactivity of both cerebral and renal arteries (both large and small vessels) by increasing p-ERK1/2 and p-PKC levels. Targeting Dusp5 may offer a novel approach for preventing hypertension-induced end-organ damage.