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Cnksr3 is a direct mineralocorticoid receptor target gene and plays a key role in the regulation of the epithelial sodium channel

Tim Ziera^*, Horst Irlbacher^*, Anja Fromm, Celine Latouche, Susanne M. Krug, Michael Fromm, Frederic Jaisser and Steffen A. Borden^*,1

^* Therapeutic Research Women’s Health, Bayer Schering Pharma AG, Berlin, Germany;

Institute of Clinical Physiology, Charité, Campus Benjamin Franklin, Freie Universität and Humboldt-Universität, Berlin, Germany; and

INSERM, U872, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris, France

¹ Correspondence: Bayer Schering Pharma AG, Müllerstr. 178, 13353 Berlin, Germany. E-mail: steffen.borden{at}bayerhealthcare.com

Aldosterone is the principal hormonal regulator of sodium homeostasis in vertebrates. It exerts its actions through the mineralocorticoid receptor (MR) that regulates the transcription of specific target genes. In recent years, a number of MR target genes have been identified that are involved in the regulation of the epithelial sodium channel (ENaC), a key modulator of renal sodium absorption. Here we report the identification of cnksr3 as a direct MR target gene that is up-regulated in response to physiological concentrations of aldosterone. The cnksr3 promoter exhibits two functional aldosterone-responsive regions, which were bound by the MR as assessed by chromatin immunoprecipitation (ChIP). In vivo, CNKSR3 was highly expressed in the renal cortical collecting duct (CCD), the prime target segment of aldosterone-regulated sodium retention in the kidney. CCD cell lines stably overexpressing or silencing CNKSR3 were electrophysiologically analyzed and show that CNKSR3 expression correlated with and is required for ENaC-mediated transepithelial sodium transport. In parallel, CNKSR3 expression led to decreased MEK phosphorylation. We conclude that CNKSR3, a homologue of scaffold proteins involved in MAPK pathway regulation, is a direct target of MR and is required for the maintenance of transepithelial sodium transport in the kidney.—Ziera, T., Irlbacher, H., Fromm, A., Latouche, C., Krug, S. M., Fromm, M., Jaisser, F., Borden, S. A. Cnksr3 is a direct mineralocorticoid receptor target gene and plays a key role in the regulation of the epithelial sodium channel.

Key Words: aldosterone • chromatin imunoprecipition • ERK/MAPK signaling • reporter gene assays • site-directed mutagenesis