Preserved Na+/H+ exchanger isoform 3 expression and localization, but decreased NHE3 function indicate regulatory sodium transport defect in ulcerative colitis

Sunil Yeruva, Klaudia Farkas, Jessica Hubricht, Katja Rode, Brigitte Riederer, Oliver Bachmann, Ayhan Cinar, Z. Rakonczay, T. Molnár, F. Nagy, Jochen Wedemeyer, Michael Manns, Dirk Raddatz, Mark W. Musch, Eugene B. Chang, P. Hegyi, Ursula Seidler

Research output: Contribution to journalArticle

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Abstract

Background: A major causative factor of diarrhea in ulcerative colitis (UC) patients is the loss of Na+ absorptive capacity of the inflamed colonic mucosa. Potential contributing mechanisms include reduced driving force for active transport, and impaired expression, mislocalization, or defective transport function of Na+ absorptive proteins. We therefore studied the expression, brush border membrane (BBM) localization, and transport capacity of the major intestinal Na+ absorptive protein, the Na +/H+ exchanger isoform 3 (NHE3) in biopsies from UC patients. Methods: In UC and control biopsies, inflammation was graded histologically, NHE3, tumor necrosis factor alpha (TNF-α), villin, as well as other housekeeping genes were analyzed by quantitative real-time polymerase chain reaction (PCR), BBM localization of NHE3 determined by immunohistochemistry, and confocal microscopy. Na+ absorptive capacity was assessed by 22Na+ isotope fluxes and NHE3 transport activity measured microfluorometrically in BCECF-loaded surface colonocytes within isolated crypts. Results: In mildly, moderately, and severely inflamed sigmoid colon of UC patients, neither NHE3 mRNA expression nor the abundance of NHE3 in the BBM was significantly altered compared to other structural components of the BBM. However, Na+ absorption was strongly reduced by ≈80% and acid-activated NHE3 transport activity was significantly decreased in the surface cells of sigmoid colonic crypts even in moderately inflamed mucosa. Conclusions: In the colonic mucosa of patients with active UC, NHE3 transport capacity was found significantly decreased despite correct NHE3 location and abundance in the brush border, independent of current treatment. These findings suggest functional NHE3 transport as a novel factor for inflammatory diarrhea in UC patients.

Original languageEnglish
Pages (from-to)1149-1161
Number of pages13
JournalInflammatory Bowel Diseases
Volume16
Issue number7
DOIs
Publication statusPublished - 2010

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Sodium-Hydrogen Antiporter
Ulcerative Colitis
Protein Isoforms
Sodium
Microvilli
Mucous Membrane
Membranes
Sigmoid Colon
Diarrhea
RNA Isoforms
Biopsy
Active Biological Transport
Essential Genes
Confocal Microscopy
Isotopes
Real-Time Polymerase Chain Reaction
Proteins
Tumor Necrosis Factor-alpha
Immunohistochemistry
Inflammation

Keywords

  • Electrolyte transport
  • Inflammatory bowel disease
  • Inflammatory diarrhea
  • Intestinal inflammation
  • Na/H exchange
  • Sodium absorption

ASJC Scopus subject areas

  • Gastroenterology
  • Immunology and Allergy

Cite this

Preserved Na+/H+ exchanger isoform 3 expression and localization, but decreased NHE3 function indicate regulatory sodium transport defect in ulcerative colitis. / Yeruva, Sunil; Farkas, Klaudia; Hubricht, Jessica; Rode, Katja; Riederer, Brigitte; Bachmann, Oliver; Cinar, Ayhan; Rakonczay, Z.; Molnár, T.; Nagy, F.; Wedemeyer, Jochen; Manns, Michael; Raddatz, Dirk; Musch, Mark W.; Chang, Eugene B.; Hegyi, P.; Seidler, Ursula.

In: Inflammatory Bowel Diseases, Vol. 16, No. 7, 2010, p. 1149-1161.

Research output: Contribution to journalArticle

Yeruva, S, Farkas, K, Hubricht, J, Rode, K, Riederer, B, Bachmann, O, Cinar, A, Rakonczay, Z, Molnár, T, Nagy, F, Wedemeyer, J, Manns, M, Raddatz, D, Musch, MW, Chang, EB, Hegyi, P & Seidler, U 2010, 'Preserved Na+/H+ exchanger isoform 3 expression and localization, but decreased NHE3 function indicate regulatory sodium transport defect in ulcerative colitis', Inflammatory Bowel Diseases, vol. 16, no. 7, pp. 1149-1161. https://doi.org/10.1002/ibd.21183
Yeruva, Sunil ; Farkas, Klaudia ; Hubricht, Jessica ; Rode, Katja ; Riederer, Brigitte ; Bachmann, Oliver ; Cinar, Ayhan ; Rakonczay, Z. ; Molnár, T. ; Nagy, F. ; Wedemeyer, Jochen ; Manns, Michael ; Raddatz, Dirk ; Musch, Mark W. ; Chang, Eugene B. ; Hegyi, P. ; Seidler, Ursula. / Preserved Na+/H+ exchanger isoform 3 expression and localization, but decreased NHE3 function indicate regulatory sodium transport defect in ulcerative colitis. In: Inflammatory Bowel Diseases. 2010 ; Vol. 16, No. 7. pp. 1149-1161.
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abstract = "Background: A major causative factor of diarrhea in ulcerative colitis (UC) patients is the loss of Na+ absorptive capacity of the inflamed colonic mucosa. Potential contributing mechanisms include reduced driving force for active transport, and impaired expression, mislocalization, or defective transport function of Na+ absorptive proteins. We therefore studied the expression, brush border membrane (BBM) localization, and transport capacity of the major intestinal Na+ absorptive protein, the Na +/H+ exchanger isoform 3 (NHE3) in biopsies from UC patients. Methods: In UC and control biopsies, inflammation was graded histologically, NHE3, tumor necrosis factor alpha (TNF-α), villin, as well as other housekeeping genes were analyzed by quantitative real-time polymerase chain reaction (PCR), BBM localization of NHE3 determined by immunohistochemistry, and confocal microscopy. Na+ absorptive capacity was assessed by 22Na+ isotope fluxes and NHE3 transport activity measured microfluorometrically in BCECF-loaded surface colonocytes within isolated crypts. Results: In mildly, moderately, and severely inflamed sigmoid colon of UC patients, neither NHE3 mRNA expression nor the abundance of NHE3 in the BBM was significantly altered compared to other structural components of the BBM. However, Na+ absorption was strongly reduced by ≈80{\%} and acid-activated NHE3 transport activity was significantly decreased in the surface cells of sigmoid colonic crypts even in moderately inflamed mucosa. Conclusions: In the colonic mucosa of patients with active UC, NHE3 transport capacity was found significantly decreased despite correct NHE3 location and abundance in the brush border, independent of current treatment. These findings suggest functional NHE3 transport as a novel factor for inflammatory diarrhea in UC patients.",
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T1 - Preserved Na+/H+ exchanger isoform 3 expression and localization, but decreased NHE3 function indicate regulatory sodium transport defect in ulcerative colitis

AU - Yeruva, Sunil

AU - Farkas, Klaudia

AU - Hubricht, Jessica

AU - Rode, Katja

AU - Riederer, Brigitte

AU - Bachmann, Oliver

AU - Cinar, Ayhan

AU - Rakonczay, Z.

AU - Molnár, T.

AU - Nagy, F.

AU - Wedemeyer, Jochen

AU - Manns, Michael

AU - Raddatz, Dirk

AU - Musch, Mark W.

AU - Chang, Eugene B.

AU - Hegyi, P.

AU - Seidler, Ursula

PY - 2010

Y1 - 2010

N2 - Background: A major causative factor of diarrhea in ulcerative colitis (UC) patients is the loss of Na+ absorptive capacity of the inflamed colonic mucosa. Potential contributing mechanisms include reduced driving force for active transport, and impaired expression, mislocalization, or defective transport function of Na+ absorptive proteins. We therefore studied the expression, brush border membrane (BBM) localization, and transport capacity of the major intestinal Na+ absorptive protein, the Na +/H+ exchanger isoform 3 (NHE3) in biopsies from UC patients. Methods: In UC and control biopsies, inflammation was graded histologically, NHE3, tumor necrosis factor alpha (TNF-α), villin, as well as other housekeeping genes were analyzed by quantitative real-time polymerase chain reaction (PCR), BBM localization of NHE3 determined by immunohistochemistry, and confocal microscopy. Na+ absorptive capacity was assessed by 22Na+ isotope fluxes and NHE3 transport activity measured microfluorometrically in BCECF-loaded surface colonocytes within isolated crypts. Results: In mildly, moderately, and severely inflamed sigmoid colon of UC patients, neither NHE3 mRNA expression nor the abundance of NHE3 in the BBM was significantly altered compared to other structural components of the BBM. However, Na+ absorption was strongly reduced by ≈80% and acid-activated NHE3 transport activity was significantly decreased in the surface cells of sigmoid colonic crypts even in moderately inflamed mucosa. Conclusions: In the colonic mucosa of patients with active UC, NHE3 transport capacity was found significantly decreased despite correct NHE3 location and abundance in the brush border, independent of current treatment. These findings suggest functional NHE3 transport as a novel factor for inflammatory diarrhea in UC patients.

AB - Background: A major causative factor of diarrhea in ulcerative colitis (UC) patients is the loss of Na+ absorptive capacity of the inflamed colonic mucosa. Potential contributing mechanisms include reduced driving force for active transport, and impaired expression, mislocalization, or defective transport function of Na+ absorptive proteins. We therefore studied the expression, brush border membrane (BBM) localization, and transport capacity of the major intestinal Na+ absorptive protein, the Na +/H+ exchanger isoform 3 (NHE3) in biopsies from UC patients. Methods: In UC and control biopsies, inflammation was graded histologically, NHE3, tumor necrosis factor alpha (TNF-α), villin, as well as other housekeeping genes were analyzed by quantitative real-time polymerase chain reaction (PCR), BBM localization of NHE3 determined by immunohistochemistry, and confocal microscopy. Na+ absorptive capacity was assessed by 22Na+ isotope fluxes and NHE3 transport activity measured microfluorometrically in BCECF-loaded surface colonocytes within isolated crypts. Results: In mildly, moderately, and severely inflamed sigmoid colon of UC patients, neither NHE3 mRNA expression nor the abundance of NHE3 in the BBM was significantly altered compared to other structural components of the BBM. However, Na+ absorption was strongly reduced by ≈80% and acid-activated NHE3 transport activity was significantly decreased in the surface cells of sigmoid colonic crypts even in moderately inflamed mucosa. Conclusions: In the colonic mucosa of patients with active UC, NHE3 transport capacity was found significantly decreased despite correct NHE3 location and abundance in the brush border, independent of current treatment. These findings suggest functional NHE3 transport as a novel factor for inflammatory diarrhea in UC patients.

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KW - Intestinal inflammation

KW - Na/H exchange

KW - Sodium absorption

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