Effect of Angiotensin II on ENaC in the Distal Convoluted Tubule and in the Cortical Collecting Duct of Mineralocorticoid Receptor Deficient Mice

J Am Heart Assoc. 2020 Apr 7;9(7):e014996. doi: 10.1161/JAHA.119.014996. Epub 2020 Mar 25.


Background Angiotensin II stimulates epithelial Na+ channel (ENaC) by aldosterone-independent mechanism. We now test the effect of angiotensin II on ENaC in the distal convoluted tubule (DCT) and cortical collecting duct (CCD) of wild-type (WT) and kidney-specific mineralocorticoid receptor knockout mice (KS-MR-KO). Methods and Results We used electrophysiological, immunoblotting and renal-clearance methods to examine the effect of angiotensin II on ENaC in KS-MR-KO and wild-type mice. High K+ intake stimulated ENaC in the late DCT/early connecting tubule (DCT2/CNT) and in the CCD whereas low sodium intake stimulated ENaC in the CCD but not in the DCT2/CNT. The deletion of MR abolished the stimulatory effect of high K+ and low sodium intake on ENaC, partially inhibited ENaC in DCT2/CNT but almost abolished ENaC activity in the CCD. Application of losartan inhibited ENaC only in DCT2/CNT of both wild-type and KS-MR-KO mice but not in the CCD. Angiotensin II infusion for 3 days has a larger stimulatory effect on ENaC in the DCT2/CNT than in the CCD. Three lines of evidence indicate that angiotensin II can stimulate ENaC by MR-independent mechanism: (1) angiotensin II perfusion augmented ENaC expression in KS-MR-KO mice; (2) angiotensin II stimulated ENaC in the DCT2/CNT but to a lesser degree in the CCD in KS-MR-KO mice; (3) angiotensin II infusion augmented benzamil-induced natriuresis, increased the renal K+ excretion and corrected hyperkalemia of KS-MR-KO mice. Conclusions Angiotensin II-induced stimulation of ENaC occurs mainly in the DCT2/CNT and to a lesser degree in the CCD and MR plays a dominant role in determining ENaC activity in the CCD but to a lesser degree in the DCT2/CNT.

Keywords: AT1R; aldosterone; hyperkalemia; hypertension.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Epithelial Sodium Channels / metabolism*
  • Hyperkalemia / drug therapy
  • Hyperkalemia / genetics
  • Hyperkalemia / metabolism
  • Hyperkalemia / physiopathology
  • Kidney Tubules, Collecting / drug effects*
  • Kidney Tubules, Collecting / metabolism
  • Kidney Tubules, Collecting / physiopathology
  • Kidney Tubules, Distal / drug effects*
  • Kidney Tubules, Distal / metabolism
  • Kidney Tubules, Distal / physiopathology
  • Membrane Potentials
  • Mice, Knockout
  • Natriuresis / drug effects
  • Potassium / urine
  • Receptor, Angiotensin, Type 1 / agonists*
  • Receptor, Angiotensin, Type 1 / metabolism
  • Receptors, Mineralocorticoid / deficiency*
  • Receptors, Mineralocorticoid / genetics
  • Renal Elimination / drug effects


  • Epithelial Sodium Channels
  • Nr3c2 protein, mouse
  • Receptor, Angiotensin, Type 1
  • Receptors, Mineralocorticoid
  • Angiotensin II
  • Potassium