TABLE 1.
NHE isoforms, their locations, (patho)physiological impact, and relevant references.
| NHE isoforms | Digestive organ | Physiological purpose/Expression/(Mal)Function | Pathological manifestation | References |
| NHE1 | Esophagus | • To protect esophageal cells from the detrimental effects of gastric acid • Basolateral acidification of extracellular space and tissue damage • Increased NHE1 expression/activity defends intracellular pH • Na+-dependent Ca2+-extrusion • Proliferation, migration, invasion, and apoptosis |
• GERD • GERD • Barrett’s esophagus • Esophageal adenocarcinoma • ESCC |
Shallat et al., 1995; Park et al., 2015 Shallat et al., 1995; Siddique and Khan, 2003 Fitzgerald et al., 1998; Ostrowski et al., 2007; Goldman et al., 2010; Laczko et al., 2016 Goldman et al., 2011; Guan et al., 2014 Ariyoshi et al., 2017 |
| NHE1 | Stomach | • Initiation of cell migration during gastric epithelial restitution • Not essential for mouse gastric epithelial repair • Insulin-like growth factor II-induced proliferation and carbachol-/insulin-like growth factor II-stimulated migration in human gastric myofibroblasts • Proliferation, migration, and invasion of gastric cancer cells |
• Gastric epithelial repair • Gastric epithelial repair • Gastric epithelial repair • Gastric cancer |
Paehler Vor der Nolte et al., 2017 Xue et al., 2011 Czepán et al., 2012 Liu et al., 2008; He et al., 2010; Nagata et al., 2011; Hosogi et al., 2012; Xia et al., 2016; Xie et al., 2017 |
| NHE1 | Intestine | • NHE1-mediated Na+ absorption • NHE1 expression was inhibited • Down-regulated in colon • Up-regulated in colon • Up-regulated in colon |
• Shiga toxin 1 induced diarrhea • Rotavirus induced diarrhea in children • UC, CD • UC, CD • DMH-induced CRC |
Laiko et al., 2010 Lorrot and Vasseur, 2007; Chen H. et al., 2017 Khan et al., 2003; Sullivan et al., 2009 Khan et al., 1998; Farkas et al., 2011 Goodison et al., 1999; Yonemura et al., 1999; Bourguignon et al., 2004 |
| NHE1 | Liver | • Up-regulated • Up-regulated • NHE1 correlates with tumor size, invasiveness and tumor progression |
• NAFLD • Hepatic ischemia injury • HCC |
Prasad et al., 2013 Levitsky et al., 1998; Wang et al., 2003 Yang et al., 2010; Yang et al., 2011 |
| NHE1 | Pancreas | • Locally acidic extracellular conditions favor tumor cell invasion | • PDAC | Rakonczay et al., 2006; Ivanov, 2008; Olszewski and Hamilton, 2009; Olszewski et al., 2010 |
| NHE2 | Stomach | • Completion of cell migration during gastric epithelial restitution • Trefoil factor peptides in mouse gastric epithelial restitution requires NHE2 activity • Parietal cell differentiation and longevity |
• Gastric epithelial repair • Gastric epithelial repair • NHE2 deficiency is accompanied by a strong, but not total loss of parietal cells the murine stomach |
Paehler Vor der Nolte et al., 2017 Xue et al., 2011; Matthis et al., 2019 Schultheis et al., 1998a; Boivin et al., 2000 |
| NHE2 | Intestine | • NHE2 activity inhibited • Down-regulated • Mediates only butyrate- dependent Na+ absorption |
• Cholera toxin induced diarrhea • TNBS-induced colitis in rats • DSS-induced ulcerative colitis |
Subramanya et al., 2007 Soleiman et al., 2017 Rajendran et al., 2015 |
| NHE3 | Intestine | • The major Na+ importer | • ETEC induced diarrhea | Hecht et al., 2004 |
| • NHE3 activity and protein expression was inhibited | • Cholera toxin induced diarrhea | Subramanya et al., 2007 | ||
| • Sodium absorption and acid secretion in human colon | • Clostridium difficile induced antibiotic-associated diarrhea | Hayashi et al., 2004; Engevik et al., 2015 | ||
| • Down-regulated | • IBD in patients or mice | Sullivan et al., 2009; Yeruva et al., 2010; Farkas et al., 2011; Lenzen et al., 2012, 2018 | ||
| NHE3 | Liver | • Decreased expression of NHE3 in cholangiocytes | • Cholestasis and liver fibrosis | Roussa et al., 2006 |
| NHE3 | Gallbladder | • Increased level of NHE3 phosphorylated at serine-552 | • Cholesterol gallstone | Chen Y. et al., 2017 |
| NHE3 | Pancreatic duct | • In murine pancreatic ducts CFTR controls expression and regulates activity of NHE3 | • NHE3 contributes to abnormal pancreatic secretion in cystic fibrosis in mice | Ahn et al., 2001 |
| NHE4 | Stomach | • In the basolateral membrane of parietal cells, the differentiation of gastric epithelial cells and the secretion of gastric acid | • NHE4 deficiency in mice causes a decrease in parietal cell number, a loss of mature chief cells, and an increase in the number of mucous and undifferentiated cells | Gawenis et al., 2005 |
| NHE4 | Intestine | • NHE4 activity can be reduced | • Escherichia coli heat-stable enterotoxin induced diarrhea | Beltrán et al., 2015 |
| NHE6 | Intestine | • NHE6 expression was inhibited | • Rotavirus induced diarrhea in children | Lorrot and Vasseur, 2007; Chen H. et al., 2017 |
| NHE8 | Stomach | • In the apical membrane of the stomach’s surface mucous cells, bicarbonate secretion and gastric epithelial repair | • NHE8 deficiency causes a decrease in gastric mucosal surface pH and an increased incidence of gastric ulcer | Xu et al., 2013 |
| NHE8 | Intestine | • Mucosa protection, mucus secretion | • NHE8 deficiency causes increased inflammation/inflammatory cytokines | Xu et al., 2012; Wang et al., 2015 |
| NHE8 | Intestine | • Controls Wnt/β-catenin signaling and Lgr5 expression | • NHE8 deficiency promotes CRC | Xu et al., 2019 |
| NHE9 | Intestine | • Up-regulated | • CRC | Ueda et al., 2017 |
| NHA2 | Pancreas | • Clathrin-mediated endocytosis and insulin secretion in β-cells | • Pathological glucose tolerance with diminished insulin secretion | Deisl et al., 2013 |