Angiotensin AT2 receptor agonist prevents salt-sensitive hypertension in obese Zucker rats

Abstract

High-sodium intake is a risk factor for the pathogenesis of hypertension, especially in obesity. The present study is designed to investigate whether angiotensin type 2 receptor (AT2R) activation with selective agonist C21 prevents high-sodium diet (HSD)-induced hypertension in obese animals. Male obese rats were treated with AT2R agonist C21 (1 mg·kg(-1)·day(-1), oral) while maintained on either normal-sodium diet (NSD; 0.4%) or HSD (4%) for 2 wk. Radiotelemetric recording showed a time-dependent increase in systolic blood pressure in HSD-fed obese rats, being maximal increase (∼27 mmHg) at day 12 of the HSD regimen. C21 treatment completely prevented the increase in blood pressure of HSD-fed rats. Compared with NSD controls, HSD-fed obese rats had greater natriuresis/diuresis and urinary levels of nitrates, and these parameters were further increased by C21 treatment. Also, C21 treatment improved glomerular filtration rate in HSD-fed rats. HSD-fed rats expressed higher level of cortical ANG II, which was reduced to 50% by C21 treatment. HSD feeding and/or C21 treatment had no effects on cortical renin activity and the expression of angiotensin-converting enzyme (ACE) and chymase, which are ANG II-producing enzymes. However, ANG(1-7) concentration and ACE2 activity in the renal cortex were reduced by HSD feeding, and C21 treatment rescued both the parameters. Also, C21 treatment reduced the cortical expression of AT1R in HSD-fed rats, but had no effect of AT2R expression. We conclude that chronic treatment with the AT2R agonist C21 prevents salt-sensitive hypertension in obese rats, and a reduction in the renal ANG II/AT1R and enhanced ACE2/ANG(1-7) levels may play a potential role in this phenomenon.

Keywords: blood pressure; compound 21; high-sodium diet; obesity.

Fig. 1.

Schematic representation of the protocol used in the study.

Fig. 2.

Systolic blood pressure of control and C21-treated obese rats fed with either normal- or high-sodium diet (HSD) for 2 wk. @Significantly different compared with control rats. #Significantly different from HSD obese rats. Values are means ± SE; 1-way ANOVA followed by Newman-Keuls test, P < 0.05; n = 5 in each group. CT, obese control; C21, obese treated with C21; HSD, obese treated with HSD; HSD+C21, obese treated with C21 and HSD.

Fig. 3.

Expression of angiotensin type 1 receptor (AT₁R; A) and AT₂R (B) in the kidney cortex of control and C21-treated obese rats fed with either normal-sodium diet or HSD. Top panels: representative Western blots for respective proteins with loading control β-actin. Bar graphs: represent the ratio of densities of the respective protein bands and β-actin, i.e., AT₁/β-actin, AT₂/β-actin. #Significantly different compared with obese HSD-treated rats. Values are means ± SE; 1-way ANOVA followed by Newman-Keuls test, P < 0.05; n = 5 in each group.

Fig. 4.

Renin activity (A), chymase expression (B), angiotensin-converting enzyme (ACE) expression (C), ACE2 activity (D), and ANG II (E) and ANG(1–7) (F) peptide levels in the kidney cortex of control and C21-treated obese rats fed with either normal-sodium diet or HSD. Top panels: representative Western blots for the respective proteins with loading control β-actin. Bar graphs: represent the ratio of densities of the respective protein bands and β-actin, i.e., ACE/β-actin, chymase/β-actin. @Significantly different compared with control rats. #Significantly different from HSD obese rats. Values are means ± SE; 1-way ANOVA followed by Newman-Keuls test, P < 0.05; n = 5 in each group.