CONICET | Buscador de Institutos y Recursos Humanos

Abstract?The use of antagonists of the mineralocorticoid receptor in the treatment of myocardial hypertrophy and heartfailure has gained increasing importance in the last years. The cardiac Na/H exchanger (NHE-1) upregulation inducedby aldosterone could account for the genesis of these pathologies. We tested whether aldosterone-induced NHE-1stimulation involves the transactivation of the epidermal growth factor receptor (EGFR). Rat ventricular myocytes wereused to measure intracellular pH with epifluorescence. Aldosterone enhanced the NHE-1 activity. This effect wascanceled by spironolactone or eplerenone (mineralocorticoid receptor antagonists), but not by mifepristone (glucocorticoidreceptor antagonist) or cycloheximide (protein synthesis inhibitor), indicating that the mechanism is mediated bythe mineralocorticoid receptor triggering nongenomic pathways. Aldosterone-induced NHE-1 stimulation was abolishedby the EGFR kinase inhibitor AG1478, suggesting that is mediated by transactivation of EGFR. The increase in thephosphorylation level of the kinase p90RSK and NHE-1 serine703 induced by aldosterone was also blocked by AG1478.Exogenous epidermal growth factor mimicked the effects of aldosterone on NHE-1 activity. Epidermal growth factorwas also able to increase reactive oxygen species production, and the epidermal growth factor?induced activation of theNHE-1 was abrogated by the reactive oxygen species scavenger N-2-mercaptopropionyl glycine, indicating that reactiveoxygen species are participating as signaling molecules in this mechanism. Aldosterone enhances the NHE-1 activityvia transactivation of the EGFR, formation of reactive oxygen species, and phosphorylation of the exchanger. Theseresults call attention to the consideration of the EGFR as a new potential therapeutic target of the cardiovascularpathologies involving the participation of aldosterone. (Hypertension. 2011;58:912-919.)