Regulation of angiotensin II receptor AT1 subtypes in renal afferent arterioles during chronic changes in sodium diet.

Abstract

Studies determined the effects of chronic changes in sodium diet on the expression, regulation, and function of different angiotensin II (ANG II) receptor subtypes in renal resistance vessels. Rats were fed low-or high-sodium diets for 3 wk before study. Receptor function was assessed in vivo by measuring transient renal blood flow responses to bolus injections of ANG II (2 ng) into the renal artery. ANG II produced less pronounced renal vasoconstriction in rats fed a low-compared with high-sodium diet (16% vs. 56% decrease in renal blood flow, P Ͻ 0.001). After acute blockade of ANG II formation by iv enalaprilat injection in sodiumrestricted animals, ANG II produced a 40% decrease in renal blood flow, a level between untreated dietary groups and less than high salt diet. Intrarenal administration of angiotensin II receptor type 1 (AT 1 ) receptor antagonists losartan or EXP-3174 simultaneously with ANG II caused dosedependent inhibition of ANG II responses. Based on maximum vasoconstriction normalized to 100% ANG II effect in each group, AT 1 receptor antagonists produced the same degree of blockade in all groups, with an apparent maximum of 80-90%. In contrast, similar doses of the angiotensin II receptor type 2 (AT 2 ) receptor ligand CGP-42112 had only a weak inhibitory effect. In vitro equilibrium-saturation 125 I-ANG II binding studies on freshly isolated afferent arterioles indicated that ANG II receptor density was lower in the low-vs. high-sodium animals (157 vs. 298 fmol/mg, P Ͻ 0.04); affinity was similar (0.65 nM). Losartan and EXP-3174 displaced up to 80-90% of the ANG II binding; fractional displacement was similar in both diet groups. In contrast, the AT 2 receptor analogues PD-123319 and CGP-42112 at concentrations Ͻ 10 Ϫ 6 M had no effect on ANG II binding. RT-PCR assays revealed the expression of both angiotensin II receptor type 1A (AT 1A ) and angiotensin II receptor type 1B (AT 1B ) subtypes in freshly isolated afferent arterioles, while there was very little AT 2 receptor expression. Total AT 1 receptor mRNA expression was suppressed by low sodium intake to 66% of control levels, whereas it was increased to 132% of control by high-sodium diet, as indicated by ribonuclease protection assay. Receptor regulation was associated with parallel changes in AT 1A and AT 1B expression; the AT 1A /AT 1B ratio was stable at 3.7. We conclude that AT 1 receptors are the predominant ANG II receptor type in renal resistance vessels of 7-wk-old rats. Chronic changes in sodium intake caused parallel regulation of expression and amount of receptor protein of the two AT 1 receptor genes that modulate receptor function and altered reactivity of renal vessels to ANG II. ( J. Clin. Invest.

Angiotensin II Type 2 Receptor Inhibits Prorenin Processing in Juxtaglomerular Cells

“…In the absence of primary antibodies, however, no signals other than those in the nucleus were observed. These results were consistent with previous studies demonstrating an immunohistochemical localization of AT1 receptor (16)(17)(18)(19) or AT2 receptor (19) in the JG apparatus and a biochemical localization of AT2 receptor in afferent arterioles (20) which transform metaplastically into JG cells (21,22). Table 1 shows Ang II concentrations in the culture medium of untreated JG cells and the cells treated with Aogen alone, Aogen CV3317, or Aogen CV11974.…”

“…These results suggest that the overall effects of Ang II generated from Aogen are dependent on AT1 receptors. Previous studies have reported that the affinity for Ang II and the number of AT1 receptors are greater than those of AT2 receptors under physiological conditions (18,20). In the present study, confocal laser microscopy demonstrated abundant AT1 receptors and a low level of AT2 receptors in the JG cells.…”

Long-Term Inhibition of Renin-Angiotensin System Sustains Memory Function in Aged Dahl Rats

“…Indeed, angiotensin II (Ang II) receptor (type 1) density in glomeruli and the mRNA levels of renal arteries are regulated by the level of salt intake. 7 Considering these data, we hypothesize that normotensive DS fed a low-salt diet are a useful rat model to investigate vascular damage induced by the process of aging and are appropriate for studying the pathophysiological or therapeutic aspects of age-related disorders in humans.…”

Intrarenal Angiotensin II Augmentation in Angiotensin II Dependent Hypertension.

“…AT1A and AT1B mRNAs have been demonstrated in the glomerulus and all nephron segments including the proximal tubule, distal tubule, thick ascending limb and collecting ducts (17,25,27). The AT1A mRNA is the predominant subtype in all nephron segments, while the AT1B is more abundant than AT1A only in the glomerulus (25,28).…”