title: Role of nuclear factor of activated T-cells 5 in regulating hypertonic-mediated secretin receptor expression in kidney collecting duct cells.
abstract: A growing body of evidence suggests that secretin (SCT) is an important element in the osmoregulatory pathway. It is interesting to note that both SCT and its receptor (SCTR) gene are activated upon hyperosmolality in the kidney. However, the precise molecular mechanisms underlying the induction of the SCTR gene expression in response to changes in osmolality have yet to be clarified. Detailed DNA sequence analysis of the promoter regions of the SCTR gene reveals the presence of multiple osmotic response elements (ORE). The ORE is the binding site of a key osmosensitive transactivator, namely, the nuclear factor of activated T-cells 5 (NFAT5). SCTR and NFAT5 are co-expressed in the kidney cortex and medulla collecting duct cells. We therefore hypothesize that NFAT5 is responsible for modulating SCTR expression in hypertonic environments. In this study, we found hypertonicity stimulates the promoter activities and endogenous gene expression of SCTR in mouse kidney cortex collecting duct cells (M1) and inner medulla collecting duct cells (mIMCD3). The overexpression and silencing of NFAT5 further confirmed it to be responsible for the up-regulation of the SCTR gene under hypertonic conditions. A significant increase in the interaction between NFAT5 and the SCTR promoter was also observed following chromatin immunoprecipitation assay. In vivo, osmotic stress up-regulates the SCTR gene in the kidney cortex and medulla of wild-type mice, but does not do so in NFAT5(+/-) animals. Hence, this study provides comprehensive information on how NFAT5 regulates SCTR expression in different osmotic environments.
authors.affiliation: School of Biological Sciences, The University of Hong Kong, Hong Kong, China.
authors.forename: Oscar W H
authors.initials: OW
authors.lastname: Chua
authors.affiliation: School of Biological Sciences, The University of Hong Kong, Hong Kong, China.
authors.forename: Kenneth K L
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Ben C
authors.initials: BC
authors.lastname: Ko
authors.affiliation: Department of Anatomy and the State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; HBHA Research Center, Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Sookja K
authors.initials: SK
authors.lastname: Chung
authors.affiliation: School of Biological Sciences, The University of Hong Kong, Hong Kong, China.
authors.forename: Billy K C
authors.initials: BK
authors.lastname: Chow
authors.affiliation: Faculty of Health Sciences, University of Macau, Taipa, Macau, China. Electronic address: LTOLee@umac.mo.
authors.forename: Leo T O
authors.initials: LT
authors.lastname: Lee
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006982:Hypertonic Solutions / Q000494:pharmacology*; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009997:Osmotic Pressure / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D006982:Hypertonic Solutions; C492200:Nfat5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; D014157:Transcription Factors; C029937:secretin receptor
keywords: Hypertonicity; Nuclear factor of activated T-cells 5; Osmoregulation; Secretin receptor; Transcriptional regulation