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Essigke, D. ; Kalo, M.Z.* ; Janessa, A.* ; Bohnert, B.N. ; Li, X.* ; Birkenfeld, A.L. ; Artunc, F.

Impact of aldosterone deficiency on the development of diuretic resistance in mice.

Pflugers Arch., DOI: 10.1007/s00424-025-03082-8 (2025)
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The effect of diuretics can be limited by stimulation of counter-regulatory mechanisms, eventually leading to diuretic resistance. It is thought that the mineralocorticoid aldosterone might contribute to the development of diuretic resistance. To test this, we challenged genetically modified mice with or without a deletion of the gene coding for the aldosterone synthase (AS) with furosemide, hydrochlorothiazide (HCT) and triamterene. Urinary excretion was studied in metabolic cages; kidneys were studied for expression of sodium transporters. In both genotypes, a 4-day treatment with HCT via drinking water (400 mg/l) induced a similar natriuresis and modest loss of body weight < 10%. In contrast, furosemide (125 mg/l) and triamterene (200 mg/l) via drinking water stimulated a significantly higher natriuresis and body weight loss in AS-/- mice and in addition, triamterene caused massive hyperkalemia > 9 mM and acidosis (pH < 7.0). In AS+/+ mice, plasma aldosterone concentration tended to increase under furosemide and HCT administration, while triamterene induced a robust ~ sixfold increase. In the kidney, apical targeting and proteolytic activation of the epithelial sodium channel ENaC were stimulated in AS+/+ mice under triamterene treatment, an effect that was diminished in AS-/- mice. In conclusion, aldosterone is essentially involved in the development of diuretic resistance to ENaC blockade by triamterene and to a lesser extent to furosemide. In contrast, resistance to HCT was independent of aldosterone.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords (mesh): Aldosterone ; Aldosterone Synthase ; Diuretics ; Furosemide ; Hydrochlorothiazide ; Triamterene; Epithelial Sodium-channel; Gamma-enac; Cl-cotransporter; Na+; Expression; Homeostasis; Mechanisms; Serum; Mouse; Localization
ISSN (print) / ISBN 0031-6768
e-ISSN 1432-2013
Journal Pflügers Archiv
Publisher Springer
Publishing Place Tiergartenstrasse 17, D-69121 Heidelberg, Germany
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)
Grants Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
Projekt DEAL