The actions of angiotensin II type 2 receptor (AT2R) and the receptor Mas (MasR) are complex but show similar pro-natriuretic function; particularly AT2R expression and natriuretic function are enhanced in obese/diabetic rat kidney. In light of some reports suggesting a potential positive interaction between these receptors, we tested hypothesis that renal AT2R and MasR physically interact and are inter-dependent to stimulate cell signaling and promote natriuresis in obese rats. We found that infusion of AT2R agonist C21 in obese Zucker rats (OZR) increased urine flow (UF) and urinary Na-excretion (UNaV) which were attenuated by simultaneous infusion of the AT2R antagonist PD123319 or the MasR antagonist A-779. Similarly, infusion of MasR agonist Ang-(1-7) in OZR increased UF and UNaV, which were attenuated by simultaneous infusion of A-779 or PD123319. Experiment in isolated renal proximal tubules of OZR revealed that both the agonists C21 and Ang-(1-7) stimulated NO which was blocked by either of the receptor antagonists. Dual-labeling of AT2R and MasR in OZR kidney sections and human proximal tubule epithelial cells showed that AT2R and MasR are colocalized. The AT2R also co-immunoprecipitated with MasR in cortical homogenate of OZR. Immunoblotting of cortical homogenate cross-linked with zero length oxidative (sulfhydryl groups) cross-linker cupric-phenanthroline revealed a shift of AT2R and MasR bands upward with overlapping migration for their complexes which were sensitive to the reducing β-mercaptoethanol, suggesting involvement of –SH groups in cross linking. Collectively, the study reveals that AT2R and MasR are co-localized and functionally interdependent in terms of stimulating NO and promoting diuretic-natriuretic response.
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.
Oxidative and nitrosative stress have been implicated in high sodium diet (HSD)-related hypertensive renal injury. In the present study we investigated AT2R-mediated renoprotection in obese Zucker rats fed HSD. Obese Zucker rats were fed normal sodium-diet (NSD) or HSD 4%, for 14 days, with/without AT2R agonist C21, delivered subcutaneously via osmotic pump, 1 mg/kg/day. Compared to NSD controls, HSD rats exhibited increase in cortical NADPH oxidase activity, urinary H2O2 and 8-isoprostanes, which were associated with severe glomerulosclerosis, interstitial fibrosis, decline in estimated glomerular filtration rate (eGFR), and an increase in urinary leak and activity of N-acetyl-β-D-glucosaminidase, a lysosomal enzyme and a marker of tubular damage. These changes were improved by C21 treatment. Cortical expression of endothelial nitric oxide synthase (eNOS), p-eNOS (Ser1177) and plasma nitrites were reduced after HSD intake while nitrosative stress (3-nitrotyrosine) and enzymatic defense (superoxide dismutase-to-catalase activity) remained unaltered. Albeit, C21 preserved plasma nitrites in HSD-fed OZR. C21 treatment reduced protein-to-creatinine (uPcr), albumin-to-creatinine (uAcr) as well as fractional excretion of protein (FEpro) and albumin (FEalb) in HSD-fed OZR, which is independent of changes in protein recycling receptors, megalin and cubilin. HSD intake also altered renal excretory and reabsorptive capacity as evident by elevated plasma urea nitrogen-to-creatinine (UN-to-cr) and fractional excretion of urea nitrogen (FEUN), and reduced urine-to-plasma creatinine (UPcr), which were modestly, but insignificantly, improved by C21 treatment. Together results demonstrate that AT2R activation protects against HSD-induced kidney damage in obesity plausibly by reducing NOX activity and rescuing nitrites.
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