The elevated blood pressure of human GRK4γ A142V transgenic mice is not associated with increased ROS production
American Journal of Physiology - Heart and Circulatory Physiology
G protein-coupled receptor kinases; hGRK4 polymorphism; Hypertension; Reactive oxygen species
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) GRK4γ A142V on a mixed genetic background (C57BL/6J and SJL/J) have impaired renal D1-dopamine receptor (D 1R) function and increased blood pressure. We now report that hGRK4γ A142V transgenic mice, in C57BL/6J background, are hypertensive and have higher blood pressures than hGRK4γ 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 hGRK4γ A142V transgenic mice and D5R 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 hGRK4γ A142V transgenic mice and their controls. HO-1 expression was increased in hGRK4γ A142V relative to hGRK4γ wild-type transgenic mice. In contrast with the hypotensive effect of Tempol in D5-/- mice, it had no effect in hGRK4γ A142V transgenic mice. We conclude that the elevated blood pressure of hGRK4γ A142V transgenic mice is due mainly to the effect of hGRK4γ A142V transgene acting via D1R and increased ROS production is not a contributor.
Wang, Z., Armando, I., Asico, L., Escano, C., Wang, X., Lu, Q., Felder, R., Schnackenberg, C., Sibley, D., Eisner, G., & Jose, P. (2007). The elevated blood pressure of human GRK4γ A142V transgenic mice is not associated with increased ROS production. American Journal of Physiology - Heart and Circulatory Physiology, 292 (5). http://dx.doi.org/10.1152/ajpheart.00944.2006