Xiao Chun Li, Chih-Hong Wang, Rumana Hassan, Akemi Sato, Ryosuke Sato, Jia L Zhuo
{"title":"Deletion of AT<sub>1a</sub> receptors selectively in the proximal tubules alters the hypotensive and natriuretic response to ANP via NPR<sub>A</sub>/cGMP/NO Signaling.","authors":"Xiao Chun Li, Chih-Hong Wang, Rumana Hassan, Akemi Sato, Ryosuke Sato, Jia L Zhuo","doi":"10.1152/ajprenal.00160.2024","DOIUrl":null,"url":null,"abstract":"<p><p>In the kidney, vasoactive peptide hormones angiotensin II (Ang II), via AT<sub>1a</sub> receptors, and atrial natriuretic peptide (ANP), via NPR<sub>A</sub> receptors, reportedly play counteracting roles to regulate proximal tubule Na<sup>+</sup> reabsorption and maintain blood pressure homeostasis. However, how AT<sub>1a</sub> and NPR<sub>A</sub> receptors interact in the proximal tubules and whether deletion of AT<sub>1</sub> (AT<sub>1a</sub>) receptors selectively in the proximal tubules alters the hypotensive and natriuretic effects of ANP) have not been studied previously. The present study used a novel mouse model with proximal tubule-specific knockout of AT<sub>1a</sub> receptors to test the hypothesis that deletion of AT<sub>1a</sub> receptors selectively in the proximal tubules augments the hypotensive and natriuretic responses to ANP. Basal blood pressure was about 16 ± 3 mmHg lower, fractional proximal tubule Na<sup>+</sup> reabsorption was significantly lower, whereas 24 h urinary Na<sup>+</sup> excretion was significantly higher in PT-<i>Agtr1a</i><sup>-/-</sup> than in wild-type mice (<i>P</i><0.01). Infusion of ANP for 2 weeks (0.5 mg/kg/day, i.p.) further significantly decreased blood pressure and increased the natriuretic response in PT-<i>Agtr1a</i><sup>-/-</sup> mice by inhibiting proximal tubule Na<sup>+</sup> reabsorption (<i>P</i><0.01). These augmented hypotensive and natriuretic responses to ANP in PT-<i>Agtr1a</i><sup>-/-</sup> mice were associated with increased plasma and kidney cGMP levels (<i>P</i><0.01), kidney cortical NPR<sub>A</sub> and NPR<sub>C</sub> mRNA expression (<i>P</i><0.01), total and phosphorylated endothelial nitric oxide synthase (eNOS) (<i>P</i><0.01), and urinary nitric oxide (NO) excretion (<i>P</i><0.01). Taken together, the results of the present study support important physiological roles of Ang II/AT<sub>1a</sub> and ANP/NPR<sub>A</sub> signaling pathways in the proximal tubules to regulate proximal tubule reabsorption and maintain blood pressure homeostasis.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Renal physiology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1152/ajprenal.00160.2024","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
In the kidney, vasoactive peptide hormones angiotensin II (Ang II), via AT1a receptors, and atrial natriuretic peptide (ANP), via NPRA receptors, reportedly play counteracting roles to regulate proximal tubule Na+ reabsorption and maintain blood pressure homeostasis. However, how AT1a and NPRA receptors interact in the proximal tubules and whether deletion of AT1 (AT1a) receptors selectively in the proximal tubules alters the hypotensive and natriuretic effects of ANP) have not been studied previously. The present study used a novel mouse model with proximal tubule-specific knockout of AT1a receptors to test the hypothesis that deletion of AT1a receptors selectively in the proximal tubules augments the hypotensive and natriuretic responses to ANP. Basal blood pressure was about 16 ± 3 mmHg lower, fractional proximal tubule Na+ reabsorption was significantly lower, whereas 24 h urinary Na+ excretion was significantly higher in PT-Agtr1a-/- than in wild-type mice (P<0.01). Infusion of ANP for 2 weeks (0.5 mg/kg/day, i.p.) further significantly decreased blood pressure and increased the natriuretic response in PT-Agtr1a-/- mice by inhibiting proximal tubule Na+ reabsorption (P<0.01). These augmented hypotensive and natriuretic responses to ANP in PT-Agtr1a-/- mice were associated with increased plasma and kidney cGMP levels (P<0.01), kidney cortical NPRA and NPRC mRNA expression (P<0.01), total and phosphorylated endothelial nitric oxide synthase (eNOS) (P<0.01), and urinary nitric oxide (NO) excretion (P<0.01). Taken together, the results of the present study support important physiological roles of Ang II/AT1a and ANP/NPRA signaling pathways in the proximal tubules to regulate proximal tubule reabsorption and maintain blood pressure homeostasis.