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Author Notes:

Correspondence: U. Seidler, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany, e-mail: seidler.ursula@mh-hannover.de

Conception and design of the experiments: S.Y., C.C.Y., and U.S.; collection, analysis, and interpretation of data: S.Y., G.Ch., L.M., M.C., A.C., L.L., M. L., J.G., A.K.S., B.R., O.B., A.B..., M.G., D.B., P.H., S.H., and U.S.; drafting the article S.Y., G.Ch., B.R., and U.S.; and revising it critically for important intellectual content: B.R., A.B..., M.G., C.C.Y., S.H., and U.S. All authors approved the final version of the manuscript.

We thank Regina Engelhardt, Brigitte Rausch, Natascha Cirpka, Silke Thiele, and Denise Renner for their help with the animal breeding and genotyping, and we thank the endoscopy team from the Department of Gastroenterology, Hepatology and Endocrinology for their dedication in biopsy acquisition.

We thank Andrew Short for helpful suggestions regarding language, clarity, and style.

The authors have no conflict of interest to disclose.

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Research Funding:

This work was supported by a grant from the German Science Foundations grants SFB621-C9 and Se460/9-6 (to U.S.) and by the Volkswagenstiftung (to U.S.) and the Hochschulinterne Leistungsförderung (HiLF) from Hannover Medical School (to S.Y.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Physiology
  • pH regulation
  • Sodium absorption
  • Electrolyte transport
  • Intestinal inflammation
  • Inflammatory bowel disease
  • INFLAMMATORY-BOWEL-DISEASE
  • INTESTINAL ION-TRANSPORT
  • ULCERATIVE-COLITIS
  • DEFICIENT MICE
  • UP-REGULATION
  • DIARRHEA
  • INHIBITION
  • EXPRESSION
  • MODEL
  • COLON

Evidence for a causal link between adaptor protein PDZK1 downregulation and Na+/H+ exchanger NHE3 dysfunction in human and murine colitis

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Journal Title:

Pflügers Archiv European Journal of Physiology

Volume:

Volume 467, Number 8

Publisher:

, Pages 1795-1807

Type of Work:

Article | Final Publisher PDF

Abstract:

A dysfunction of the Na<sup>+</sup>/H<sup>+</sup> exchanger isoform 3 (NHE3) significantly contributes to the reduced salt absorptive capacity of the inflamed intestine. We previously reported a strong decrease in the NHERF family member PDZK1 (NHERF3), which binds to NHE3 and regulates its function in a mouse model of colitis. The present study investigates whether a causal relationship exists between the decreased PDZK1 expression and the NHE3 dysfunction in human and murine intestinal inflammation. Biopsies from the colon of patients with ulcerative colitis, murine inflamed ileal and colonic mucosa, NHE3-transfected Caco-2BBe colonic cells with short hairpin RNA (shRNA) knockdown of PDZK1, and Pdzk1-gene-deleted mice were studied. PDZK1 mRNA and protein expression was strongly decreased in inflamed human and murine intestinal tissue as compared to inactive disease or control tissue, whereas that of NHE3 or NHERF1 was not. Inflamed human and murine intestinal tissues displayed correct brush border localization of NHE3 but reduced acid-activated NHE3 transport activity. A similar NHE3 transport defect was observed when PDZK1 protein content was decreased by shRNA knockdown in Caco-2BBe cells or when enterocyte PDZK1 protein content was decreased to similar levels as found in inflamed mucosa by heterozygote breeding of Pdzk1-gene-deleted and WT mice. We conclude that a decrease in PDZK1 expression, whether induced by inflammation, shRNA-mediated knockdown, or heterozygous breeding, is associated with a decreased NHE3 transport rate in human and murine enterocytes. We therefore hypothesize that inflammation-induced loss of PDZK1 expression may contribute to the NHE3 dysfunction observed in the inflamed intestine.

Copyright information:

© 2014, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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