Abstract: SA-PO1034
High Chloride Silences Aldosterone Signaling in the Distal Nephron
Session Information
- Fluid and Electrolytes: Basic - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid and Electrolytes
- 901 Fluid and Electrolytes: Basic
Authors
- Ehmke, Heimo, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Meyer-Schwesinger, Catherine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Vitzthum, Helga, University Medical Center Hamburg-Eppendorf (UKE) , Hamburg, Germany
Background
The adrenal steroid hormone aldosterone plays a primary role in maintaining normal body electrolyte homeostasis. Physiologically, aldosterone secretion from the adrenal glands is under the control of angiotensin II and plasma [K+]. Surprisingly, high aldosterone levels due to high K+ intake are normally not associated with renal salt retention and disturbances of systemic Na+ and Cl- homeostasis. K+ supplementation consistently enhances renal Na+ excretion in animals as well as in humans particularly during NaCl loading when Na+ delivery to the distal nephron is high. We therefore questioned whether a further mechanism may exist which in the context of a high NaCl and high K+ intake attenuates the aldosterone-MR-ENaC pathway.
Methods
We analyzed the effects of a normal or high K+ diet on Na+ excretion, MR localization, ENaC mRNA and protein expression, and ENaC activity in salt replete mice. The effects of high extracellular chloride concentration [Cl-] on MR localization and ENaC expression was also determined in mCCD cells, a cellular model of principal cells in the collecting duct.
Results
The canonical cellular responses to aldosterone, encompassing translocation of the mineralocorticoid receptor (MR), transcription and activation of epithelial sodium channel ENaC, and ENaC-dependent Na+ reabsorption, were undetectable in mice receiving a high K+ /high NaCl diet in spite of increased plasma aldosterone concentrations. Elevating extracellular chloride concentration [Cl-] was sufficient to suppress the aldosterone-induced MR translocation and ENaC protein expression in vitro and in vivo. Functionally and biochemically, the aldosterone response was rescued in vivo when the extracellular [Cl-] increase was prevented during the high K+ diet.
Conclusion
These findings show that aldosterone signaling in the kidney is silenced by increased extracellular [Cl-] and provide an explanation for the natriuretic effect of a high K+ intake in the presence of a high NaCl consumption characteristic for the Western diet.
Funding
- Government Support - Non-U.S.