Compromised regulation of the collecting duct ENaC activity in mice lacking AT1a receptor

Mykola Mamenko, Oleg Zaika, Viktor Tomilin, V. Behrana Jensen, Oleh Pochynyuk

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

ENaC-mediated sodium reabsorption in the collecting duct (CD) is a critical determinant of urinary sodium excretion. Existing evidence suggest direct stimulatory actions of Angiotensin II (Ang II) on ENaC in the CD, independently of the aldosterone-mineralocorticoid receptor (MR) signaling. Deletion of the major renal AT1 receptor isoform, AT1aR, decreases blood pressure and reduces ENaC abundance despite elevated aldosterone levels. The mechanism of this insufficient compensation is not known. Here, we used patch clamp electrophysiology in freshly isolated split-opened CDs to investigate how AT1aR dysfunction compromises functional ENaC activity and its regulation by dietary salt intake. Ang II had no effect on ENaC activity in CDs from AT1aR −/− mice suggesting no complementary contribution of AT2 receptors. We next found that AT1aR deficient mice had lower ENaC activity when fed with low (<0.01% Na+) and regular (0.32% Na+) but not with high (∼2% Na+) salt diet, when compared to the respective values obtained in Wild type (WT) animals. Inhibition of AT1R with losartan in wild-type animals reproduces the effects of genetic ablation of AT1aR on ENaC activity arguing against contribution of developmental factors. Interestingly, manipulation with aldosterone-MR signaling via deoxycosterone acetate (DOCA) and spironolactone had much reduced influence on ENaC activity upon AT1aR deletion. Consistently, AT1aR −/− mice have a markedly diminished MR abundance in cytosol. Overall, we conclude that AT1aR deficiency elicits a complex inhibitory effect on ENaC activity by attenuating ENaC Po and precluding adequate compensation via aldosterone cascade due to decreased MR availability.

Original languageEnglish (US)
Pages (from-to)7217-7225
Number of pages9
JournalJournal of Cellular Physiology
Volume233
Issue number9
DOIs
StatePublished - Sep 2018

Keywords

  • Mas
  • Na reabsorption
  • aldosterone
  • distal renal tubule
  • mineralocorticoid receptors

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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