Amelioration of genetic hypertension by suppression of renal G protein-coupled receptor kinase type 4 expression.
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.
Sanada
Hironobu
H
Department of Internal Medicine III, Fukushima Medical University School of Medicine, Fukushima, Japan.
Yatabe
Junichi
J
Midorikawa
Sanae
S
Katoh
Tetsuo
T
Hashimoto
Shigeatsu
S
Watanabe
Tsuyoshi
T
Xu
Jing
J
Luo
Yingjin
Y
Wang
Xiaoyan
X
Zeng
Chunyu
C
Armando
Ines
I
Felder
Robin A
RA
Jose
Pedro A
PA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004231:Diuresis; D054771:G-Protein-Coupled Receptor Kinase 4; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009318:Natriuresis; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D012694:Serine; D012964:Sodium / Q000378:metabolism; D014018:Tissue Distribution
D016376:Oligonucleotides, Antisense; D017447:Receptors, Dopamine D1; D012694:Serine; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human; C517854:Grk4 protein, rat