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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
Author(s) -
Ziera Tim,
Irlbacher Horst,
Fromm Anja,
Latouche Celine,
Krug Susanne M.,
Fromm Michael,
Jaisser Frederic,
Borden Steffen A.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-134759
Subject(s) - epithelial sodium channel , mineralocorticoid receptor , aldosterone , chromatin immunoprecipitation , mineralocorticoid , microbiology and biotechnology , sodium channel , gene silencing , sgk1 , transcription factor , biology , medicine , downregulation and upregulation , homeostasis , chemistry , sodium , gene expression , endocrinology , gene , phosphorylation , promoter , biochemistry , organic chemistry
ABSTRACT 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 physio‐logical 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 overexpress‐ing 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. FASEB J. 23, 3936‐3946 (2009). www.fasebj.org