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

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.

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