Loss of NHE8 expression impairs intestinal mucosal integrity

Wang, Aiping; Li, Jing; Zhao, Yang; Johansson, Malin; Xu, Hua

doi:10.1152/ajpgi.00278.2015

Cited by 36 publications

(36 citation statements)

References 43 publications

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“…SLC9A8 (solute carrier family 9 member A8) encodes a transmembrane protein that exchanges extracellular Na þ for intracellular H þ (37). It has been reported to be involved in intestinal mucosal integrity by regulating the functions of goblet and Paneth cells (38), and its loss has been shown to result in reduced mucin Mean normalized allelic fraction (mNAF) and mutation significance in the MiSeq data shown for the 71 genes selected for screening (Sets A, B, and C) in the extended set. Color indicates the mutation frequency of the gene, with darker shades corresponding to higher frequencies.…”

Section: Aasdhmentioning

confidence: 99%

Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

et al. 2017

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Approximately 15% of colorectal cancers exhibit microsatellite instability (MSI), which leads to accumulation of large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in microsatellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite. Therefore, assessing the general impact of mismatch repair deficiency on the likelihood of mutation events is paramount when following this approach. To identify MSI target genes, we developed a statistical model for the somatic background indel mutation rate of microsatellites to assess mutation significance. Exome sequencing data of 24 MSI colorectal cancers revealed indels at 54 million mononucleotide microsatellites of three or more nucleotides in length. The top 105 microsatellites from 71 genes were further analyzed in 93 additional MSI colorectal cancers. Mutation significance and estimated clonality of mutations determined the most likely MSI target genes to be the aminoadipate-semialdehyde dehydrogenase and the solute transporter Our findings offer a systematic profiling of the somatic background mutation rate in protein-coding mononucleotide microsatellites, allowing a full cataloging of the true targets of MSI in colorectal cancer. .

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Section: Aasdhmentioning

confidence: 99%

Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

et al. 2017

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“…NHE8 may compensate for the loss of NHE2 and NHE3 in knockout mice, suggesting the role of NHE8 in the intestinal sodium absorption in early life, when NHE2 ND NHE3 are at very low levels (316). Targeted ablation of the Slc9a8 gene in mice results in a higher incidence of gastric ulcer formation, impaired mucosal protection, and altered gut microbiota (177, 300, 315, 317, 321), pointing to the role of NHE8 in mucosal protection in the gut.…”

Section: Mammalian Monovalent Cation Proton Antiporter Superfamilymentioning

confidence: 99%

“…Goblet cells express NHE8, which is downregulated in rodent experimental colitis and in UC patients, and its deletion confers higher susceptibility with an enhanced T-helper 2–like response (174, 177, 311). Reduced expression or absence of NHE8 also leads to decreased Muc2 mRNA expression in goblets cells, and decreased mucosal expression of antimicrobial peptides (300). Reduced Muc2 expression is also detected in NHE8 −/− goblet cells and in intestinal organoids from Nhe8 -deficient mice (Xu et al, unpublished data).…”

Section: Na+/h+ Exchange In Pathological Statesmentioning

confidence: 99%

SLC9 Gene Family: Function, Expression, and Regulation

Kiela

2018

Comprehensive Physiology

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The Slc9 family of Na /H exchangers (NHEs) plays a critical role in electroneutral exchange of Na and H in the mammalian intestine as well as other absorptive and secretory epithelia of digestive organs. These transport proteins contribute to the transepithelial Na and water absorption, intracellular pH and cellular volume regulation as well as the electrolyte, acid-base, and fluid volume homeostasis at the systemic level. They also influence the function of other membrane transport mechanisms, affect cellular proliferation and apoptosis as well as cell migration, adherence to the extracellular matrix, and tissue repair. Additionally, they modulate the extracellular milieu to facilitate other nutrient absorption and to regulate the intestinal microbial microenvironment. Na /H exchange is inhibited in selected gastrointestinal diseases, either by intrinsic factors (e.g., bile acids, inflammatory mediators) or infectious agents and associated bacterial toxins. Disrupted NHE activity may contribute not only to local and systemic electrolyte imbalance but also to the disease severity via multiple mechanisms. In this review, we describe the cation proton antiporter superfamily of Na /H exchangers with a particular emphasis on the eight SLC9A isoforms found in the digestive tract, followed by a more integrative description in their roles in each of the digestive organs. We discuss regulatory mechanisms that determine the function of Na /H exchangers as pertinent to the digestive tract, their regulation in pathological states of the digestive organs, and reciprocally, the contribution of dysregulated Na /H exchange to the disease pathogenesis and progression. © 2018 American Physiological Society. Compr Physiol 8:555-583, 2018.

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“…Moreover, its expression is not limited to the apical membrane; in vitro studies with ectopically expressed NHE8 have shown that it is both present and functional in the trans-Golgi network and multivesicular bodies 113 . It is broadly expressed in the colon, including the goblet cells, where it participates in the regulation of mucin 2 (Muc2) expression and mucous secretion 41, 114, 115. Although we observed a dramatic decrease in the expression of NHE8 in UC patients (Li et al, unpublished data), loss of NHE8 expression and activity may not contribute to inflammation-associated diarrhea directly because NHE8 -/- mice do not show symptoms of impaired Na + absorption or diarrhea 41 .…”

Section: Intestinal Na+/h+ Exchange In Clinical and Experimental Inflmentioning

confidence: 99%

“…Indeed, it is down-regulated and confers higher susceptibility during experimental colitis with a T-helper 2–like response 151, 152. Reduced expression or absence of NHE8 also is related to decreased Muc2 mRNA expression in goblets cells, and decreased mucosal expression of antimicrobial peptides 114 . NHE8 -/- mice have reduced Muc2 expression, which also could be reproduced in colonic organoids from this strain (Xu et al, unpublished data), and show a reduced inner mucous layer and closer proximity of luminal bacteria to the brush-border membrane 152 .…”

Section: Intestinal Na+/h+ Exchange In Clinical and Experimental Inflmentioning

confidence: 99%

Pathophysiology of Intestinal Na+/H+ Exchange

Gurney

Laubitz

Ghishan

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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Several members of the SLC9A family of Na+/H+ exchangers are expressed in the gut, with varying expression patterns and cellular localization. Not only do they participate in the regulation of basic epithelial cell functions, including control of transepithelial Na+ absorption, intracellular pH (pHi), cell volume, and nutrient absorption, but also in cellular proliferation, migration, and apoptosis. Additionally, they modulate the extracellular milieu in order to facilitate other nutrient absorption and to regulate the intestinal microbial microenvironment. Na+/H+ exchangers are frequent targets of inhibition in gastrointestinal pathologies, either by intrinsic factors (e.g. bile acids, inflammatory mediators) or infectious agents and associated microbial toxins. Based on emerging evidence, disruption of NHE activity via impaired expression or function of respective isoforms may contribute not only to local and systemic electrolyte imbalance, but also to the disease severity via multiple mechanisms. Here, we review the current state of knowledge about the roles Na+/H+ exchangers play in the pathogenesis of disorders of diverse origin and affecting a range of GI tissues.

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Loss of NHE8 expression impairs intestinal mucosal integrity

Cited by 36 publications

References 43 publications

Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

SLC9 Gene Family: Function, Expression, and Regulation

Pathophysiology of Intestinal Na+/H+ Exchange

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