title: Experimental colitis is associated with transcriptional inhibition of Na+/Ca2+ exchanger isoform 1 (NCX1) expression by interferon γ in the renal distal convoluted tubules.
abstract: NCX1 is a Na(+)/Ca(2+) exchanger, which is believed to provide a key route for basolateral Ca(2+) efflux in the renal epithelia, thus contributing to renal Ca(2+) reabsorption. Altered mineral homeostasis, including intestinal and renal Ca(2+) transport may represent a significant component of the pathophysiology of the bone mineral density loss associated with Inflammatory Bowel Diseases (IBD). The objective of our research was to investigate the effects of TNBS and DSS colitis and related inflammatory mediators on renal Ncx1 expression. Colitis was associated with decreased renal Ncx1 expression, as examined by real-time RT-PCR, Western blotting, and immunofluorescence. In mIMCD3 cells, IFNγ significantly reduced Ncx1 mRNA and protein expression. Similar effects were observed in cells transiently transfected with a reporter construct bearing the promoter region of the kidney-specific Ncx1 gene. This inhibitory effect of IFNγ is mediated by STAT1 recruitment to the proximal promoter region of Ncx1. Further in vivo study with Stat1(-/-) mice confirmed that STAT1 is indeed required for the IFNγ mediated Ncx1 gene regulation. These results strongly support the hypothesis that impaired renal Ca(2+) handling occurs in experimental colitis. Negative regulation of NCX1- mediated renal Ca(2+) absorption by IFNγ may significantly contribute to the altered Ca(2+) homeostasis in IBD patients and to IBD-associated loss of bone mineral density.
authors: From the Departments of Pediatrics, Steele Children's Research Center and.
authors: Vijayababu M
authors: VM
authors: Radhakrishnan
authors: From the Departments of Pediatrics, Steele Children's Research Center and.
authors: Pawel
authors: P
authors: Kojs
authors: From the Departments of Pediatrics, Steele Children's Research Center and.
authors: Rajalakshmy
authors: R
authors: Ramalingam
authors: From the Departments of Pediatrics, Steele Children's Research Center and.
authors: Monica T
authors: MT
authors: Midura-Kiela
authors: Zanvyl Krieger School of Arts and Sciences Johns Hopkins University, Baltimore, Maryland 21218.
authors: Peter
authors: P
authors: Angeli
authors: From the Departments of Pediatrics, Steele Children's Research Center and Immunobiology, University of Arizona Health Sciences Center, Tucson, Arizona 85724, and.
authors: Pawel R
authors: PR
authors: Kiela
authors: From the Departments of Pediatrics, Steele Children's Research Center and fghishan@peds.arizona.edu.
authors: Fayez K
authors: FK
authors: Ghishan
mesh_terms: D000818:Animals; D001483:Base Sequence; D003092:Colitis / Q000235:genetics*; D017931:DNA Primers; D007371:Interferon-gamma / Q000378:metabolism*; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger; D007371:Interferon-gamma
keywords: colitis; distal convoluted tubule; epithelial transport; gene transcription; inflammatory bowel disease (IBD); interferon; kidney; signal transducers and activators of transcription 1 (STAT1); sodium-calcium exchange
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