title: The diuretic torasemide does not prevent aldosterone-mediated mineralocorticoid receptor activation in cardiomyocytes.
abstract: Aldosterone binds to the mineralocorticoid receptor (MR) and exerts pleiotropic effects beyond enhancing renal sodium reabsorption. Excessive mineralocorticoid signaling is deleterious during the evolution of cardiac failure, as evidenced by the benefits provided by adding MR antagonists (MRA) to standard care in humans. In animal models of cardiovascular diseases, MRA reduce cardiac fibrosis. Interestingly diuretics such as torasemide also appear efficient to improve cardiovascular morbidity and mortality, through several mechanisms. Among them, it has been suggested that torasemide could block aldosterone binding to the MR. To evaluate whether torasemide acts as a MRA in cardiomyocytes, we compared its effects with a classic MRA such as spironolactone. We monitored ligand-induced nuclear translocation of MR-GFP and MR transactivation activity in the cardiac-like cell line H9C2 using a reporter gene assay and known endogenous aldosterone-regulated cardiac genes. Torasemide did not modify MR nuclear translocation. Aldosterone-induced MR transactivation activity was reduced by the MRA spironolactone, not by torasemide. Spironolactone blocked the induction by aldosterone of endogenous MR-responsive genes (Sgk-1, PAI-1, Orosomucoid-1, Rgs-2, Serpina-3, Tenascin-X), while torasemide was ineffective. These results show that torasemide is not an MR antagonist; its association with MRA in heart failure may however be beneficial, through actions on complementary pathways.
authors.affiliation: INSERM Unité 872, Université Pierre et Marie Curie, Team 1, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Basile
authors.initials: B
authors.lastname: Gravez
authors.forename: Antoine
authors.initials: A
authors.lastname: Tarjus
authors.forename: Ruben
authors.initials: R
authors.lastname: Jimenez-Canino
authors.forename: Soumaya
authors.initials: S
authors.lastname: El Moghrabi
authors.forename: Smail
authors.initials: S
authors.lastname: Messaoudi
authors.forename: Diego
authors.initials: D
authors.lastname: Alvarez de la Rosa
authors.forename: Frederic
authors.initials: F
authors.lastname: Jaisser
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D004232:Diuretics / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009961:Orosomucoid / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics; D013148:Spironolactone / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D019063:Tenascin / Q000235:genetics; D000077786:Torsemide; D015533:Transcriptional Activation / Q000187:drug effects; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000450:Aldosterone; D004232:Diuretics; D049452:Green Fluorescent Proteins; D017874:Immediate-Early Proteins; D008156:Luciferases; D000451:Mineralocorticoid Receptor Antagonists; D009961:Orosomucoid; D017395:Plasminogen Activator Inhibitor 1; D017346:Protein Serine-Threonine Kinases; D018161:Receptors, Mineralocorticoid; D015843:Serpins; D013148:Spironolactone; D013449:Sulfonamides; D019063:Tenascin; D000077786:Torsemide; D000099184:Serum-Glucocorticoid Regulated Kinases; C081865:tenascin X
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