title: The elevated blood pressure of human GRK4gamma A142V transgenic mice is not associated with increased ROS production.
abstract: G protein-coupled receptor (GPCR) kinases (GRKs) regulate the sensitivity of GPCRs, including dopamine receptors. The GRK4 locus is linked to, and some of its polymorphisms are associated with, human essential hypertension. Transgenic mice overexpressing human (h) GRK4gamma A142V on a mixed genetic background (C57BL/6J and SJL/J) have impaired renal D(1)-dopamine receptor (D(1)R) function and increased blood pressure. We now report that hGRK4gamma A142V transgenic mice, in C57BL/6J background, are hypertensive and have higher blood pressures than hGRK4gamma wild-type transgenic and nontransgenic mice. The hypertensive phenotype is stable because blood pressures in transgenic founders and F6 offspring are similarly increased. To determine whether the hypertension is associated with increased production of reactive oxygen species (ROS), we measured renal NADPH oxidase (Nox2 and Nox4) and heme oxygenase (HO-1 and HO-2) protein expressions and urinary excretion of 8-isoprostane and compared the effect of Tempol on blood pressure in hGRK4gamma A142V transgenic mice and D(5)R knockout (D(5)(-/-)) mice in which hypertension is mediated by increased ROS. The expressions of Nox isoforms and HO-2 and the urinary excretion of 8-isoprostane were similar in hGRK4gamma A142V transgenic mice and their controls. HO-1 expression was increased in hGRK4gamma A142V relative to hGRK4gamma wild-type transgenic mice. In contrast with the hypotensive effect of Tempol in D(5)(-/-) mice, it had no effect in hGRK4gamma A142V transgenic mice. We conclude that the elevated blood pressure of hGRK4gamma A142V transgenic mice is due mainly to the effect of hGRK4gamma A142V transgene acting via D(1)R and increased ROS production is not a contributor.
authors.affiliation: Georgetown University School of Medicine, 4000 Reservoir Road NW, Washington, DC 20057, USA. wangz10@georgetown.edu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Ines
authors.initials: I
authors.lastname: Armando
authors.forename: Laureano D
authors.initials: LD
authors.lastname: Asico
authors.forename: Crisanto
authors.initials: C
authors.lastname: Escano
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Lu
authors.forename: Robin A
authors.initials: RA
authors.lastname: Felder
authors.forename: Christine G
authors.initials: CG
authors.lastname: Schnackenberg
authors.forename: David R
authors.initials: DR
authors.lastname: Sibley
authors.forename: Gilbert M
authors.initials: GM
authors.lastname: Eisner
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D054771:G-Protein-Coupled Receptor Kinase 4; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050641:Receptors, Dopamine D5 / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D050641:Receptors, Dopamine D5; D017346:Protein Serine-Threonine Kinases; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human; C517853:GRK4 protein, mouse