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Cardiovascular-Renal Mechanisms in Health and Disease

The elevated blood pressure of human GRK4 A142V transgenic mice is not associated with increased ROS production

¹Department of Pediatrics and Physiology and Biophysics, Georgetown University School of Medicine, Washington, District of Columbia; ²Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, Virginia; ³Department of Investigative and Cardiac Biology, GlaxoSmithKline, King of Prussia, Pennsylvania; ⁴Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke/National Institutes of Health, Bethesda, Maryland; and ⁵Department of Medicine, Georgetown University Medical Center, Washington, District of Columbia

Submitted 31 August 2006 ; accepted in final form 19 January 2007

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) GRK4 A142V on a mixed genetic background (C57BL/6J and SJL/J) have impaired renal D₁-dopamine receptor (D₁R) function and increased blood pressure. We now report that hGRK4 A142V transgenic mice, in C57BL/6J background, are hypertensive and have higher blood pressures than hGRK4 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 hGRK4 A142V transgenic mice and D₅R knockout (D₅^–/–) 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 hGRK4 A142V transgenic mice and their controls. HO-1 expression was increased in hGRK4 A142V relative to hGRK4 wild-type transgenic mice. In contrast with the hypotensive effect of Tempol in D₅^–/– mice, it had no effect in hGRK4 A142V transgenic mice. We conclude that the elevated blood pressure of hGRK4 A142V transgenic mice is due mainly to the effect of hGRK4 A142V transgene acting via D₁R and increased ROS production is not a contributor.

hGRK4 polymorphism; hypertension; reactive oxygen species; G protein-coupled receptor kinases