Experimental colitis is associated with transcriptional inhibition of Na<sup>+</sup>/Ca<sup>2+</sup> 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

3 Citations (Scopus)

Abstract

NCX1is a Na<sup>+</sup>/Ca<sup>2+</sup> exchanger, which is believed to provide a key route for basolateral Ca<sup>2+</sup> efflux in the renal epithelia, thus contributingto renal Ca<sup>2+</sup> reabsorption. Altered mineral homeostasis, including intestinal and renal Ca<sup>2+</sup> 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<sup>-/-</sup> mice confirmed that STAT1 is indeed required for the IFNγ mediated Ncx1 gene regulation. These results strongly support the hypothesis that impaired renal Ca<sup>2+</sup> handling occurs in experimental colitis. Negative regulation of NCX1- mediated renal Ca<sup>2+</sup> absorption by IFNγ may significantly contribute to the altered Ca<sup>2+</sup> 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

Fingerprint

Distal Kidney Tubule
Colitis
Interferons
Minerals
Protein Isoforms
Kidney
Genetic Promoter Regions
Bone
Bearings (structural)
Inflammatory Bowel Diseases
Gene expression
Bone Density
Homeostasis
Genes
Messenger RNA
Fluorescent Antibody Technique
Real-Time Polymerase Chain Reaction
Proteins
Epithelium
Western Blotting

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Experimental colitis is associated with transcriptional inhibition of Na<sup>+</sup>/Ca<sup>2+</sup> exchanger isoform 1 (NCX1) expression by interferon γ in the renal distal convoluted tubules. / Radhakrishnan, Vijayababu M.; Kojs, Pawel; Ramalingam, Rajalakshmy; Midura-Kiela, Monica T.; Angeli, Peter; Kiela, Pawel R; Ghishan, Fayez K.

In: Journal of Biological Chemistry, Vol. 290, No. 14, 03.04.2015, p. 8964-8974.

Research output: Contribution to journalArticle

@article{a0e6504d540f491da3568bc9ab99999e,
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 = "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.",
author = "Radhakrishnan, {Vijayababu M.} and Pawel Kojs and Rajalakshmy Ramalingam and Midura-Kiela, {Monica T.} and Peter Angeli and Kiela, {Pawel R} and Ghishan, {Fayez K}",
year = "2015",
month = "4",
day = "3",
doi = "10.1074/jbc.M114.616516",
language = "English (US)",
volume = "290",
pages = "8964--8974",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "14",

}

TY - JOUR

T1 - Experimental colitis is associated with transcriptional inhibition of Na+/Ca2+ exchanger isoform 1 (NCX1) expression by interferon γ in the renal distal convoluted tubules

AU - Radhakrishnan, Vijayababu M.

AU - Kojs, Pawel

AU - Ramalingam, Rajalakshmy

AU - Midura-Kiela, Monica T.

AU - Angeli, Peter

AU - Kiela, Pawel R

AU - Ghishan, Fayez K

PY - 2015/4/3

Y1 - 2015/4/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84926443398&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84926443398&partnerID=8YFLogxK

U2 - 10.1074/jbc.M114.616516

DO - 10.1074/jbc.M114.616516

M3 - Article

C2 - 25648899

AN - SCOPUS:84926443398

VL - 290

SP - 8964

EP - 8974

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 14

ER -