title: Direct and Indirect Mineralocorticoid Effects Determine Distal Salt Transport.
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.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon; and.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Terker
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon; and.
authors.forename: Bethzaida
authors.initials: B
authors.lastname: Yarbrough
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon; and.
authors.forename: Mohammed Z
authors.initials: MZ
authors.lastname: Ferdaus
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon; and.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Lazelle
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon; and.
authors.forename: Kayla J
authors.initials: KJ
authors.lastname: Erspamer
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon; and.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Meermeier
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon; and.
authors.forename: Hae J
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon; and.
authors.forename: James A
authors.initials: JA
authors.lastname: McCormick
authors.affiliation: 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.
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: David H
authors.initials: DH
authors.lastname: Ellison
mesh_terms: D000818:Animals; D001692:Biological Transport; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D017673:Sodium Chloride, Dietary / Q000378:metabolism*
chemical_list: D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary
keywords: ENaC; aldosterone; cell signaling; epithelial sodium transport; hypokalemia