Differential effects of angiotensin II type-1 receptor antisense oligonucleotides on renal function in spontaneously hypertensive rats.
The effect of selectively decreasing renal angiotensin II type 1 (AT1) receptor expression on renal function and blood pressure has not been determined. Therefore, we studied the consequences of selective renal inhibition of AT1 receptor expression in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in vivo. Vehicle, AT1 receptor antisense oligodeoxynucleotides (AS-ODN), or scrambled oligodeoxynucleotides were infused chronically into the cortex of the remaining kidney of conscious, uninephrectomized WKY and SHR on a 4% NaCl intake. Basal renal cortical membrane AT1 receptor protein was greater in SHR than in WKY. In WKY and SHR, AS-ODN decreased renal but not cardiac AT1 receptors. AT1 receptor AS-ODN treatment increased plasma renin activity to a greater extent in WKY than in SHR. However, plasma angiotensin II and aldosterone were increased by AS-ODN to a similar degree in both rat strains. In SHR, sodium excretion was increased and sodium balance was decreased by AS-ODN but had only a transient ameliorating effect on blood pressure. Urinary protein and glomerular sclerosis were markedly reduced by AS-ODN-treated SHR. In WKY, AS-ODN had no effect on sodium excretion, blood pressure, or renal histology but also modestly decreased proteinuria. The major consequence of decreasing renal AT1 receptor protein in the SHR is a decrease in proteinuria, probably as a result of the amelioration in glomerular pathology but independent of systemic blood pressure and circulating angiotensin II levels.
Yoneda
Minoru
M
Fukushima Medical University School of Medicine, Japan.
Sanada
Hironobu
H
Yatabe
Junichi
J
Midorikawa
Sanae
S
Hashimoto
Shigeatsu
S
Sasaki
Midori
M
Katoh
Tetsuo
T
Watanabe
Tsuyoshi
T
Andrews
Peter M
PM
Jose
Pedro A
PA
Felder
Robin A
RA
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004231:Diuresis / Q000187:drug effects; D006651:Histocytochemistry; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology*; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011188:Potassium / Q000652:urine; D011507:Proteinuria / Q000503:physiopathology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism; D012083:Renin / Q000097:blood
D047228:Angiotensin II Type 1 Receptor Blockers; D016376:Oligonucleotides, Antisense; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000450:Aldosterone; D012083:Renin; D011188:Potassium