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, Zoltán; Molnár, Tamás; Nagy, Ferenc; Wedemeyer, Jochen; Manns, Michael P.; Roggenbuck, Dirk; Musch, Mark W.; Chang, Eugene B.; Hegyi, Péter; Seidler, Ursula

doi:10.1002/ibd.21183

Cited by 56 publications

(62 citation statements)

References 53 publications

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“…Interferon-γ and TNF-α decrease NHE3 activity causing diarrhea [51,145,2]. Consistent with a role in inflammatory bowel disease, NHE3 expression and/or activity is decreased in mouse models and human disease [159,187] . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 NHE3 mediates the majority of sodium reabsorption from the proximal tubule.…”

Section: Slc9a3 -Nhe3mentioning

confidence: 70%

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Fuster

Alexander

2013

Pflugers Arch - Eur J Physiol

143

122

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The SLC9 gene family encodes Na + /H + exchangers (NHEs). These transmembrane proteins transport ions across lipid bilayers in a diverse array of species from prokaryotes to eukaryotes, including plants, fungi and animals. They utilize the electrochemical gradient of one ion to transport another ion against its electrochemical gradient. Currently, 13 evolutionarily conserved NHE isoforms are known in mammals [46,22,128]. The SLC9 gene family (solute carrier classification of transporters:www.bioparadigms.org) is divided into three subgroups [46]. The SLC9A subgroup encompasses plasmalemmal isoforms NHE1-5 (SLC9A1-5) and the predominantly intracellular isoforms NHE6-9 (SLC9A6-9). The SLC9B subgroup consists of two recently cloned isoforms, NHA1 and NHA2 (SLC9B1 and SLC9B2, respectively). The SLC9C subgroup consist of a sperm specific plasmalemmal NHE (SLC9C1) and a putative NHE, SLC9C2, for which there is currently no functional data [46].NHEs participate in the regulation of cytosolic and organellar pH as well as cell volume. In the intestine and kidney, NHEs are critical for transepithelial movement of Na + and HCO 3 -and thus for whole body volume and acid-base homeostasis [46]. Mutations in the NHE6 or NHE9 genes cause neurological disease in humans and are currently the only NHEs directly linked to human disease.However, it is becoming increasingly apparent that members of this gene family contribute to the pathophysiology of multiple human diseases.

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Section: Slc9a3 -Nhe3mentioning

confidence: 70%

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Fuster

Alexander

2013

Pflugers Arch - Eur J Physiol

143

122

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“…Under physiological condition, NHE3, a brush border NHE, plays an essential role in the regulation of the acidity of the apical microenvironment (29). In the face of genetic loss of Slc9a3 in a mouse model (11,12,15,16), or significant inhibition of NHE3 expression and/or activity during the IBD progression (17,23,27,34), the resulting changes in the microbiome composition may contribute to the degree of colitis developed. Conversely, susceptibility of NHE3 Ϫ/Ϫ mice to DSS-induced mucosal injury and changes in the tight and adherens junctions (12), as well as increased epithelial cell apoptosis in NHE3/IL-10 double KO mice (15), suggest another, potentially intrinsic, epithelial cell defect, which is subject to modulation by colonic microbiota.…”

Section: G675mentioning

confidence: 99%

Reduced colonic microbial diversity is associated with colitis in NHE3-deficient mice

Larmonier

Laubitz

Hill

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…49,50 Many studies suggest that decreased gene expression/epithelial surface expression/activity of NHE3 and other sodium transporters relates to the incidence of absorptive diarrhea in IBD and animal colitis models. 39,51,52 However, other studies discount this to be the case. 51,53 CFTR remains critical to regulate electroneutral sodium chloride absorption and NHE3 regulation by augmenting its inhibition in a cAMP-dependent fashion.…”

Section: Cftr-inos Signaling Complexmentioning

confidence: 99%

“…39,51,52 However, other studies discount this to be the case. 51,53 CFTR remains critical to regulate electroneutral sodium chloride absorption and NHE3 regulation by augmenting its inhibition in a cAMP-dependent fashion. 54e56 It is interesting that the same intracellular cAMP, Ca 2þ , or cGMP that activates CFTR would inhibit NHE3.…”

Section: Cftr-inos Signaling Complexmentioning

confidence: 99%

Altered cGMP Dynamics at the Plasma Membrane Contribute to Diarrhea in Ulcerative Colitis

Arora

Sinha

Zhang

et al. 2015

The American Journal of Pathology

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Ulcerative colitis (UC) belongs to inflammatory bowel disorders, a group of gastrointestinal disorders that can produce serious recurring diarrhea in affected patients. The mechanism for UC-and inflammatory bowel disorder-associated diarrhea is not well understood. The cystic fibrosis transmembraneconductance regulator (CFTR) chloride channel plays an important role in fluid and water transport across the intestinal mucosa. CFTR channel function is regulated in a compartmentalized manner through the formation of CFTR-containing macromolecular complexes at the plasma membrane. In this study, we demonstrate the involvement of a novel macromolecular signaling pathway that causes diarrhea in UC. We found that a nitric oxide-producing enzyme, inducible nitric oxide synthase (iNOS), is overexpressed under the plasma membrane and generates compartmentalized cGMP in gut epithelia in UC. The scaffolding protein Na þ /H þ exchanger regulatory factor 2 (NHERF2) bridges iNOS with CFTR, forming CFTR-NHERF2-iNOS macromolecular complexes that potentiate CFTR channel function via the nitric oxide-cGMP pathway under inflammatory conditions both in vitro and in vivo. Potential disruption of these complexes in Nherf2 À/À mice may render them more resistant to CFTR-mediated secretory diarrhea than Nherf2 þ/þ mice in murine colitis models. Our study provides insight into the mechanism of pathophysiologic occurrence of diarrhea in UC and suggests that targeting CFTR and CFTR-containing macromolecular complexes will ameliorate diarrheal symptoms and improve conditions associated with inflammatory bowel disorders. (Am J Pathol 2015 http://dx

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

Cited by 56 publications

References 53 publications

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Reduced colonic microbial diversity is associated with colitis in NHE3-deficient mice

Altered cGMP Dynamics at the Plasma Membrane Contribute to Diarrhea in Ulcerative Colitis

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