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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\u00a0mg\/l) induced a similar natriuresis and modest loss of body weight\u2009&lt;\u200910%. In contrast, furosemide (125\u00a0mg\/l) and triamterene (200\u00a0mg\/l) via drinking water stimulated a significantly higher natriuresis and body weight loss in <jats:italic>AS<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup> mice and in addition, triamterene caused massive hyperkalemia\u2009&gt;\u20099\u00a0mM and acidosis (pH\u2009&lt;\u20097.0). In <jats:italic>AS<\/jats:italic>\n            <jats:sup>+<jats:italic>\/<\/jats:italic>+<\/jats:sup> mice, plasma aldosterone concentration tended to increase under furosemide and HCT administration, while triamterene induced a robust\u2009~\u2009sixfold increase. In the kidney, apical targeting and proteolytic activation of the epithelial sodium channel ENaC were stimulated in <jats:italic>AS<\/jats:italic>\n            <jats:sup>+<jats:italic>\/<\/jats:italic>+<\/jats:sup> mice under triamterene treatment, an effect that was diminished in <jats:italic>AS<\/jats:italic>\n            <jats:sup>\u2212<jats:italic>\/<\/jats:italic>\u2212<\/jats:sup> 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.<\/jats:p>","DOI":"10.1007\/s00424-025-03082-8","type":"journal-article","created":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T06:18:21Z","timestamp":1744438701000},"page":"827-840","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Impact of aldosterone deficiency on the development of diuretic resistance in mice"],"prefix":"10.1007","volume":"477","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1473-377X","authenticated-orcid":false,"given":"Daniel","family":"Essigke","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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