Kidney Week

Abstract: TH-OR006

Angiotensin II Stimulates ENaC by an Aldosterone-Independent Mechanism

Session Information

• Advances in Fluid and Electrolyte Handling: Basic Physiology
  November 07, 2019 | Location: 146 C, Walter E. Washington Convention Center
  Abstract Time: 05:30 PM - 05:42 PM

Category: Fluid and Electrolytes

• 901 Fluid and Electrolytes: Basic

Authors

• Wang, WenHui, New York Medical College, Valhalla, New York, United States

WenHui Wang, MD



Wen-Hui Wang, MD Professor Department of Pharmacology New York Medical College Valhalla, NY 10595 wenhui_wang@nymc.edu

• Wu, Peng, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

Peng Wu,

• Gao, Zhong-Xiuzi, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

Zhong-Xiuzi Gao,

• Terker, Andrew, OHSU, Portland, Oregon, United States

Andrew Terker,

• Zhang, Dandan, New York Medical Collage, Valhalla, China

Dandan Zhang,

• Lin, Daohong, New York Medical College, Valhalla, New York, United States

Daohong Lin,

• Ellison, David H., Oregon Health & Science University, Portland, Oregon, United States

David H. Ellison,

Background

Epithelial Na⁺ channel (ENaC) is expressed in the aldosterone-sensitive distal nephron and both aldosterone and angiotensin II (AngII) have been shown to stimulate ENaC activity. The aim of the present study is to test whether AngII is able to stimulate ENaC by an aldosterone-independent mechanism.

Methods

We employed the patch-clamp technique and renal-Na⁺ clearance method to study the effect of AngII on ENaC in the DCT and CCD of WT and kidney-specific mineralocorticoid receptor knockout (MR-KO) mice, where MR is knocked out in adult mice.

Results

High dietary K⁺ (HK) intake stimulates ENaC in both DCT and CCD in WT mice but this effect is absent in MR-KO mice. In contrast, low sodium (LS) stimulates ENaC only in the CCD but not in the DCT and the effect of LS on ENaC in the CCD was completely absent in MR-KO mice. Under control conditions the amiloride-sensitive Na⁺ currents (ENaC) in DCT2 were significantly higher than in the CCD. The deletion of MR partially inhibited ENaC in the DCT but completely abolished ENaC in the CCD. Furthermore, application of losartan (AT1R antagonist) inhibited ENaC in the DCT of both WT and MR-KO mice, suggesting the role of AT1R in regulating ENaC activity in the DCT. In contrast, losartan did not have a significant effect on ENaC in the CCD of WT mice. Infusion of AngII for 3 days increased ENaC activity in the DCT and in the CCD of WT mice. Moreover, AngII infusion still robustly increased ENaC currents in the DCT of MR-KO mice whereas the stimulatory effect of AngII on ENaC was modest in the CCD. Renal clearance study further demonstrated that angiotensin II infusion for three days augmented benzamil-induced natriuresis in MR-KO mice and increased the renal K⁺ excretion. Consequently, the infusion of AngII completely corrected hyperkalemia of MR-KO mice.

Conclusion

Angiotensin II-induced stimulation of ENaC occurs mainly in the DCT and to a lesser degree in the CCD. In contrast, aldosterone plays a dominant role in determining ENaC activity in the CCD but to a lesser degree in the DCT. Thus, AT1R plays an important role in the regulation of ENaC activity in the DCT.

Funding

• NIDDK Support