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Early Nongenomic Events in Aldosterone Action in Renal Collecting Duct Cells: PKC Activation, Mineralocorticoid Receptor Phosphorylation, and Cross-Talk with the Genomic Response

Cathy Le Moëllic^*, Antoine Ouvrard-Pascaud^*, Claudia Capurro, Francoise Cluzeaud^*, Michel Fay^*, Frederic Jaisser^*, Nicolette Farman^* and Marcel Blot-Chabaud^*

*INSERM U478, Institut Claude Bernard "Physiologie et Pathologie," Faculté de Médecine Xavier Bichat, Paris, France; and Laboratorio de Biomembranas, Departamento de Fisiologia, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.

Correspondence to Dr. Cathy le Moëllic, INSERM U478, Faculté de Médecine Xavier Bichat, BP 416, 75870 PARIS, Cedex 18, France. Phone: 331-44856325; Fax: 331-42291644; E-mail: moellic{at}bichat.inserm.fr; or M. Blot-Chabaud, Phone: 334-91835685: Fax: 334-91835602;

ABSTRACT. Effects of aldosterone on its target cells have long been considered to be mediated exclusively through the genomic pathway; however, evidence has been provided for rapid effects of the hormone that may involve nongenomic mechanisms. Whether an interaction exists between these two signaling pathways is not yet established. In this study, the authors show that aldosterone triggers both early nongenomic and late genomic increase in sodium transport in the RCCD₂ rat cortical collecting duct cell line. In these cells, the early (up to 2.5 h) aldosterone-induced increase in short-circuit current (Isc) is not blocked by the mineralocorticoid receptor (MR) antagonist RU26752, it does not require mRNA or protein synthesis, and it involves the PKC signaling pathway. In addition, this early response is reproduced by aldosterone-BSA, which acts at the cell surface and presumably does not enter the cells (aldo-BSA is unable to trigger the late response). The authors also show that MR is rapidly phosphorylated on serine and threonine residues by aldosterone or aldosterone-BSA. In contrast, the late (4 to 24 h) aldosterone-induced increase in ion transport occurs through activation of the MR and requires mRNA and protein synthesis. Interestingly, nongenomic and genomic aldosterone actions appear to be interdependent. Blocking the PKC pathway results in the inhibition of the late genomic response to aldosterone, as demonstrated by the suppression of aldosterone-induced increase in MR transactivation activity, 1 Na⁺/K⁺/ATPase mRNA, and Isc. These data suggest cross-talk between the nongenomic and genomic responses to aldosterone in renal cells and suggest that the aldosterone-MR mediated increase in mRNA/protein synthesis and ion transport depends, at least in part, upon PKC activation. E-mail: marcel.blot-chabaud@pharmacie.univ-mrs.fr

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