Dataset Information

Identification of a Primary Renal AT₂ Receptor Defect in Spontaneously Hypertensive Rats.

ABSTRACT:

Rationale

Previous studies identified a defect in Ang III (angiotensin III [des-aspartyl¹-angiotensin II])-elicited AT₂R (Ang type-2 receptor)-mediated natriuresis in renal proximal tubule cells of spontaneously hypertensive rats (SHR).

Objective

This study aimed to delineate in prehypertensive SHR kidneys the receptor or postreceptor defect causing impaired AT₂R signaling and renal sodium (Na⁺) retention by utilizing the selective AT₂R agonist compound-21 (C-21).

Methods and results

Female 4-week-old Wistar Kyoto and SHR rats were studied after 24-hour systemic AT₁R (Ang II type-1 receptor) blockade. Left kidneys received 30-minute renal interstitial infusions of vehicle followed by C-21 (20, 40, and 60 ng/[kg·min], each dose 30 minutes). Right kidneys received vehicle infusions. In Wistar Kyoto, C-21 dose-dependently increased urine Na⁺ excretion from 0.023±0.01 to 0.064±0.02, 0.087±0.01, and 0.089±0.01 µmol/min (P=0.008, P<0.0001, and P<0.0001, respectively) and renal interstitial fluid levels of AT₂R downstream signaling molecule cGMP (cyclic guanosine 3',5' monophosphate) from 0.91±0.3 to 3.1±1.0, 5.9±1.2 and 5.3±0.5 fmol/mL (P=nonsignificant, P<0.0001, and P<0.0001, respectively). In contrast, C-21 did not increase urine Na⁺ excretion or renal interstitial cGMP in SHR. Mean arterial pressure was slightly higher in SHR but within the normotensive range and unaffected by C-21. In Wistar Kyoto, but not SHR, C-21 induced AT₂R translocation to apical plasma membranes of renal proximal tubule cells, internalization/inactivation of NHE-3 (sodium-hydrogen exchanger-3) and Na⁺/K⁺ATPase (sodium-potassium-atpase) and phosphorylation of AT₂R-cGMP downstream signaling molecules Src (Src family kinase), ERK (extracellular signal-related kinase), and VASP (vasodilator-stimulated phosphoprotein). To test whether cGMP could bypass the natriuretic defect in SHR, we infused 8-bromo-cGMP. This restored natriuresis, Na⁺ transporter internalization/inactivation, and Src and VASP phosphorylation, but not apical plasma membrane AT₂R recruitment. In contrast, 8-bromo-cAMP administration had no effect on natriuresis or AT₂R recruitment in SHR.

Conclusions

The results demonstrate a primary renal proximal tubule cell AT₂R natriuretic defect in SHR that may contribute to the development of hypertension. Since the defect is abrogated by exogenous intrarenal cGMP, the renal cGMP pathway may represent a viable target for the treatment of hypertension. Visual Overview: An online visual overview is available for this article.

SUBMITTER: Kemp BA

PROVIDER: S-EPMC7112539 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Identification of a Primary Renal AT<sub>2</sub> Receptor Defect in Spontaneously Hypertensive Rats.

Kemp Brandon A BA Howell Nancy L NL Gildea John J JJ Keller Susanna R SR Carey Robert M RM

Circulation research 20200130 5

<h4>Rationale</h4>Previous studies identified a defect in Ang III (angiotensin III [des-aspartyl<sup>1</sup>-angiotensin II])-elicited AT<sub>2</sub>R (Ang type-2 receptor)-mediated natriuresis in renal proximal tubule cells of spontaneously hypertensive rats (SHR).<h4>Objective</h4>This study aimed to delineate in prehypertensive SHR kidneys the receptor or postreceptor defect causing impaired AT<sub>2</sub>R signaling and renal sodium (Na<sup>+</sup>) retention by utilizing the selective AT<su ...[more]

PMID: 31997705

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Project description:Aims:Current antihypertensive therapies cannot cure hypertension and a life-long medication is necessary. Maternal treatment may represent a promising strategy for hypertension treatment. We have previously shown that maternal treatment of spontaneously hypertensive rats (SHR) with pentaerythritol tetranitrate (PETN) leads to a persistent blood pressure reduction in the female offspring. The underlying mechanisms include improved endothelial function resulting from long-lasting epigenetic changes. In the present study, we address the renal effects of maternal PETN treatment. Methods and Results:F0 parental SHR were fed with either normal chow or PETN-containing (1 g/kg) chow ad libitum from the time point of mating to the end of lactation period. The F1 offspring received normal chow without PETN from the time point of weaning (at the age of 3 weeks). At the age of 16 weeks, female PETN offspring showed lower blood pressure than the control. No difference was observed in male offspring. All following experiments were performed with kidneys from 16-week-old female offspring. Maternal PETN treatment reduced the mRNA and protein expression of angiotensin-converting enzyme (ACE) and basic fibroblast growth factor (FGF2), resulting from epigenetic modifications found at the proximal promoter regions. The expression levels of mineralocorticoid receptor (MR) and factors in the MR signalling pathway (Rac1 and Sgk1) were also reduced by PETN. Major profibrotic cytokines, including Wnt4, TNF-alpha, TGF-beta, and MMP9, were downregulated by PETN, which was associated with reduced collagen deposition and glomerulus sclerosis in the kidney of PETN offspring. In addition, PETN treatment also decreased the markers of inflammation and immune cell infiltration in the kidneys. Conclusions:PETN maternal treatment leads to epigenetic changes in the kidney of female SHR offspring. The reduced renal inflammation, alleviated kidney fibrosis, and decreased MR signalling are potential mechanisms contributing to the observed blood pressure-lowering effect.

Project description:BackgroundRadiofrequency ablation of the renal arteries (RF-ABL) has been shown to decrease blood pressure (BP) in drug-resistant hypertensive patients who receive antihypertensive drug therapy. However, there remain questions regarding how RF-ABL influences BP independent of drug therapy and whether complete renal denervation is necessary to maximally lower BP. To study these questions, we examined the cardiovascular, sympathetic, and renal effects produced by RF-ABL of the proximal renal arteries in spontaneously hypertensive rats (SHR) with established hypertension.MethodsSHR were instrumented (telemetry) for measurement of systolic/diastolic BP (SBP/DBP). Rats then underwent Sham-ABL or RF-ABL adjacent to the renal ostium and BP was recorded for 8 weeks. Changes in sympathetic activity, 24-hour water/sodium excretion, and levels of urinary angiotensinogen (AGT), plasma renin activity, and kidney renin content (KRC) were measured in SHR.ResultsCompared with Sham-ABL, RF-ABL produced a sustained decrease in BP. At 8 weeks, SBP/DBP was 171±6/115±3 and 183±4/129±3mm Hg for RF-ABL and Sham-ABL SHR, respectively. Correlating with the reduction in BP, RF-ABL significantly decreased the low frequency/total and low frequency/high frequency of BP variability and attenuated the hypotensive response to chlorisondamine. Kidney norepinephrine levels were markedly decreased at 8 weeks in RF-ABL vs. Sham-ABL SHR. There were no group differences in 24-hour sodium/water excretion or urinary AGT excretion rate (6 weeks) or plasma renin activity or KRC (8 weeks). In other studies, concurrent RF-ABL plus surgical denervation initially decreased BP to a greater level than RF-ABL alone, but thereafter the reduction in BP between groups was not different.ConclusionsIn hypertensive SHR, bilateral RF-ABL of the proximal renal arteries produced a sustained decease in sympathetic activity and BP without changes in sodium/water excretion or activity of the systemic/renal renin-angiotensin system.

Dataset Information

Identification of a Primary Renal AT₂ Receptor Defect in Spontaneously Hypertensive Rats.

Rationale

Objective

Methods and results

Conclusions

Publications

Identification of a Primary Renal AT<sub>2</sub> Receptor Defect in Spontaneously Hypertensive Rats.

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Rationale

Objective

Methods and results

Conclusions

Publications

Identification of a Primary Renal AT<sub>2</sub> Receptor Defect in Spontaneously Hypertensive Rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Identification of a Primary Renal AT₂ Receptor Defect in Spontaneously Hypertensive Rats.