Published Online
on June 13, 2005

A more recent version of this article appeared on July 1, 2005

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Submitted on January 26, 2005
Revised on February 25, 2005

Differential Effects of Angiotensin II Type-1 Receptor Antisense Oligonucleotides on Renal Function in Spontaneously Hypertensive Rats

Minoru Yoneda; Hironobu Sanada; Junichi Yatabe; Sanae Midorikawa; Shigeatsu Hashimoto; Midori Sasaki; Tetsuo Katoh; Tsuyoshi Watanabe; Peter M. Andrews; Pedro A. Jose^*; and Robin A. Felder

From the Fukushima Medical University School of Medicine (M.Y., H.S., J.Y., S.M., S.H., M.S., T.K., T.W.), Japan; Georgetown University Medical Center (P.M.A., P.A.J.), Washington, DC; and University of Virginia Health Sciences Center (R.A.F.), Charlottesville.

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

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.

Key words: receptors, angiotensin II • rats • kidney • hypertension, essential • proteinuria

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