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J Am Soc Nephrol. 2016 Aug;27(8):2436-45. doi: 10.1681/ASN.2015070815. Epub 2015 Dec 28.

Direct and Indirect Mineralocorticoid Effects Determine Distal Salt Transport.

Author information

1
Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon; and.
2
Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon; and Renal Section, Veterans Affairs Portland Health Care System, Portland, Oregon.
3
Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon; and Renal Section, Veterans Affairs Portland Health Care System, Portland, Oregon ellisond@ohsu.edu.

Abstract

Excess aldosterone is an important contributor to hypertension and cardiovascular disease. Conversely, low circulating aldosterone causes salt wasting and hypotension. Aldosterone activates mineralocorticoid receptors (MRs) to increase epithelial sodium channel (ENaC) activity. However, aldosterone may also stimulate the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC). Here, we generated mice in which MRs could be deleted along the nephron to test this hypothesis. These kidney-specific MR-knockout mice exhibited salt wasting, low BP, and hyperkalemia. Notably, we found evidence of deficient apical orientation and cleavage of ENaC, despite the salt wasting. Although these mice also exhibited deficient NCC activity, NCC could be stimulated by restricting dietary potassium, which also returned BP to control levels. Together, these results indicate that MRs regulate ENaC directly, but modulation of NCC is mediated by secondary changes in plasma potassium concentration. Electrolyte balance and BP seem to be determined, therefore, by a delicate interplay between direct and indirect mineralocorticoid actions in the distal nephron.

KEYWORDS:

ENaC; aldosterone; cell signaling; epithelial sodium transport; hypokalemia

PMID:
26712527
PMCID:
PMC4978056
DOI:
10.1681/ASN.2015070815
[Indexed for MEDLINE]
Free PMC Article

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