Published Online
on April 24, 2006

A more recent version of this article appeared on June 1, 2006

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Submitted on January 27, 2006
Revised on February 20, 2006

Amelioration of Genetic Hypertension by Suppression of Renal G Protein-Coupled Receptor Kinase Type 4 Expression

Hironobu Sanada; Junichi Yatabe; Sanae Midorikawa; Tetsuo Katoh; Shigeatsu Hashimoto; Tsuyoshi Watanabe; Jing Xu; Yingjin Luo; Xiaoyan Wang; Chunyu Zeng; Ines Armando; Robin A. Felder; and Pedro A. Jose^*

From the Department of Internal Medicine III (H.S., S.M., T.K., S.H., T.W.), Fukushima Medical University School of Medicine, Fukushima, Japan; Department of Pathology (J.Y., R.A.F.), University of Virginia Health Sciences Center, Charlottesville, Va; Department of Pediatrics and Physiology and Biophysics (J.X., Y.L., X.W., I.A., P.A.J.), Georgetown University Medical Center, Washington, DC; and Department of Cardiology (C.Z.), Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China.

^* To whom correspondence should be addressed. E-mail: pjose01{at}georgetown.edu.

Abstract--Abnormalities in D₁ dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein-coupled receptor kinase type 4 (GRK4) causes the impaired renal D₁ receptor function in hypertension. We measured renal GRK4 and D₁ and serine-phosphorylated D₁ receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious- uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar-Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D₁ receptors were 90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D₁ receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D₁ receptor control of sodium excretion and blood pressure in genetic hypertension.

Key words: kidney • blood pressure • receptors, dopamine • rats, spontaneously hypertensive

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