title: Differential effects of angiotensin II type-1 receptor antisense oligonucleotides on renal function in spontaneously hypertensive rats.
abstract: 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.
authors.affiliation: Fukushima Medical University School of Medicine, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoneda
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sanada
authors.forename: Junichi
authors.initials: J
authors.lastname: Yatabe
authors.forename: Sanae
authors.initials: S
authors.lastname: Midorikawa
authors.forename: Shigeatsu
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Midori
authors.initials: M
authors.lastname: Sasaki
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Katoh
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andrews
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
authors.forename: Robin A
authors.initials: RA
authors.lastname: Felder
mesh_terms: 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
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D016376:Oligonucleotides, Antisense; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000450:Aldosterone; D012083:Renin; D011188:Potassium