title: Aldosterone-Mediated Renal Sodium Transport Requires Intact Mineralocorticoid Receptor DNA-Binding in the Mouse.
abstract: The classic role of mineralocorticoid receptor (MR) is to promote sodium transport in epithelial tissues. However, the MR is also expressed in a range of tissues in which its role appears unrelated to sodium transport, and under normal physiological conditions, it may be responding to cortisol (corticosterone in rodents) rather than aldosterone. The relative importance of transcriptional mechanisms such as classical genomic signaling via a hormone response element, transrepression of other transcription factors, and nongenomic signaling is not clear, particularly in nonepithelial tissues. The goal of the present study was to define the role of the different signaling pathways for the MR by separating the functional role of classic genomic signaling, mediated by DNA binding, from these two other mechanisms. We used gene targeting to generate mice in which serine is substituted for cysteine at codon 603 in the MR; this mutation precludes DNA binding. These MR C603S mutant mice either die at birth or fail to thrive, lose weight, and die between days 10 and 13 in a manner similar to that observed previously for mice null for the MR gene. Renal expression and cellular localization of MR C603S by immunohistochemistry was equivalent to control mice. MR C603S mice were rescued by twice-daily saline injections. Despite increased aldosterone levels, renal expression of aldosterone-induced genes was not increased. This unique mouse model demonstrates that DNA binding is essential for the epithelial MR response and will provide the basis for analysis of nonclassical signaling of the MR in nonepithelial tissues.
authors.affiliation: Hudson Institute (L.T., J.M., M.A., Y.-Z.Y., P.J.F.) (formerly Prince Henry's Institute of Medical Research) and the Departments of Biochemistry and Molecular Biology (T.J.C., L.T., M.J.Y., P.J.F.), and Physiology (P.E., M.J.Y.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Cole
authors.affiliation: Hudson Institute (L.T., J.M., M.A., Y.-Z.Y., P.J.F.) (formerly Prince Henry's Institute of Medical Research) and the Departments of Biochemistry and Molecular Biology (T.J.C., L.T., M.J.Y., P.J.F.), and Physiology (P.E., M.J.Y.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Terella
authors.affiliation: Hudson Institute (L.T., J.M., M.A., Y.-Z.Y., P.J.F.) (formerly Prince Henry's Institute of Medical Research) and the Departments of Biochemistry and Molecular Biology (T.J.C., L.T., M.J.Y., P.J.F.), and Physiology (P.E., M.J.Y.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Morgan
authors.affiliation: Hudson Institute (L.T., J.M., M.A., Y.-Z.Y., P.J.F.) (formerly Prince Henry's Institute of Medical Research) and the Departments of Biochemistry and Molecular Biology (T.J.C., L.T., M.J.Y., P.J.F.), and Physiology (P.E., M.J.Y.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Alexiadis
authors.affiliation: Hudson Institute (L.T., J.M., M.A., Y.-Z.Y., P.J.F.) (formerly Prince Henry's Institute of Medical Research) and the Departments of Biochemistry and Molecular Biology (T.J.C., L.T., M.J.Y., P.J.F.), and Physiology (P.E., M.J.Y.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Yi-Zhou
authors.initials: YZ
authors.lastname: Yao
authors.affiliation: Hudson Institute (L.T., J.M., M.A., Y.-Z.Y., P.J.F.) (formerly Prince Henry's Institute of Medical Research) and the Departments of Biochemistry and Molecular Biology (T.J.C., L.T., M.J.Y., P.J.F.), and Physiology (P.E., M.J.Y.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Pablo
authors.initials: P
authors.lastname: Enriori
authors.affiliation: Hudson Institute (L.T., J.M., M.A., Y.-Z.Y., P.J.F.) (formerly Prince Henry's Institute of Medical Research) and the Departments of Biochemistry and Molecular Biology (T.J.C., L.T., M.J.Y., P.J.F.), and Physiology (P.E., M.J.Y.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Morag J
authors.initials: MJ
authors.lastname: Young
authors.affiliation: Hudson Institute (L.T., J.M., M.A., Y.-Z.Y., P.J.F.) (formerly Prince Henry's Institute of Medical Research) and the Departments of Biochemistry and Molecular Biology (T.J.C., L.T., M.J.Y., P.J.F.), and Physiology (P.E., M.J.Y.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Fuller
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D004247:DNA / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D055879:Gene Knock-In Techniques; D017136:Ion Transport / Q000187:drug effects / Q000235:genetics; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D004247:DNA; D012964:Sodium