title: Effect of mineralocorticoid treatment in mice with collecting duct-specific knockout of endothelin-1.
abstract: Aldosterone increases blood pressure (BP) by stimulating sodium (Na) reabsorption within the distal nephron and collecting duct (CD). Aldosterone also stimulates endothelin-1 (ET-1) production that acts within the CD to inhibit Na reabsorption via a negative feedback mechanism. We tested the hypothesis that this renal aldosterone-endothelin feedback system regulates electrolyte balance and BP by comparing the effect of a high-salt (NaCl) diet and mineralocorticoid stimulation in control and CD-specific ET-1 knockout (CD ET-1 KO) mice. Metabolic balance and radiotelemetric BP were measured before and after treatment with desoxycorticosterone pivalate (DOCP) in mice fed a high-salt diet with saline to drink. CD ET-1 KO mice consumed more high-salt diet and saline and had greater urine output than controls. CD ET-1 KO mice exhibited increased BP and greater fluid retention and body weight than controls on a high-salt diet. DOCP with high-salt feeding further increased BP in CD ET-1 KO mice, and by the end of the study the CD ET-1 KO mice were substantially hypernatremic. Unlike controls, CD ET-1 KO mice failed to respond acutely or escape from DOCP treatment. We conclude that local ET-1 production in the CD is required for the appropriate renal response to Na loading and that lack of local ET-1 results in abnormal fluid and electrolyte handling when challenged with a high-salt diet and with DOCP treatment. Additionally, local ET-1 production is necessary, under these experimental conditions, for renal compensation to and escape from the chronic effects of mineralocorticoids.
authors.affiliation: Research Service, North Florida/South Georgia Veterans Health System, Gainesville, Florida; Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, Gainesville, Florida;
authors.forename: I Jeanette
authors.initials: IJ
authors.lastname: Lynch
authors.affiliation: Research Service, North Florida/South Georgia Veterans Health System, Gainesville, Florida; Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, Gainesville, Florida; Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida;
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Welch
authors.affiliation: Research Service, North Florida/South Georgia Veterans Health System, Gainesville, Florida; Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, Gainesville, Florida; Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida; and.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Gumz
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center and Salt Lake City Veterans Affairs Medical Center, Salt Lake City, Utah.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida; and.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Cain
authors.affiliation: Research Service, North Florida/South Georgia Veterans Health System, Gainesville, Florida; Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, Gainesville, Florida; Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida; CSWingo@ufl.edu.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Wingo
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008901:Mineralocorticoids / Q000494:pharmacology*; D044023:Receptor, Endothelin B / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D008901:Mineralocorticoids; D044023:Receptor, Endothelin B; D017673:Sodium Chloride, Dietary; D012964:Sodium
keywords: aldosterone; aldosterone escape; blood pressure; desoxycorticosterone; endothelin; renal; sodium reabsorption