Experimental colitis is associated with transcriptional inhibition of Na+/Ca2+ exchanger isoform 1 (NCX1) expression by interferon γ in the renal distal convoluted tubules

Vijayababu M. Radhakrishnan, Pawel Kojs, Rajalakshmy Ramalingam, Monica T. Midura-Kiela, Peter Angeli, Pawel R. Kiela, Fayez K. Ghishan

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

NCX1is a Na+/Ca2+ exchanger, which is believed to provide a key route for basolateral Ca2+ efflux in the renal epithelia, thus contributingto renal Ca2+ reabsorption. Altered mineral homeostasis, including intestinal and renal Ca2+ 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 Ca2+ handling occurs in experimental colitis. Negative regulation of NCX1- mediated renal Ca2+ absorption by IFNγ may significantly contribute to the altered Ca2+ homeostasis in IBD patients and to IBD-associated loss of bone mineral density.

Original languageEnglish (US)
Pages (from-to)8964-8974
Number of pages11
JournalJournal of Biological Chemistry
Volume290
Issue number14
DOIs
StatePublished - Apr 3 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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