scholarly journals Somatostatin regulates NHE8 protein expression via the ERK1/2 MAPK pathway in DSS-induced colitis mice

2016 ◽  
Vol 311 (5) ◽  
pp. G954-G963 ◽  
Author(s):  
Xiao Li ◽  
Lin Cai ◽  
Hua Xu ◽  
Chong Geng ◽  
Jing Lu ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Somatostatin Receptor ◽  
Mucosal Injury ◽  
Sodium Absorption ◽  
Colonic Tissue ◽  
Pathological Conditions ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger ◽  
First Time ◽  
Stimulation Of

Previous studies reported that administration of somatostatin (SST) to human patients mitigated their diarrheal symptoms. Octreotide (an analog of SST) treatment in animals resulted in upregulation of sodium/hydrogen exchanger 8 (NHE8). NHE8 is important for water/sodium absorption in the intestine, and loss of NHE8 function results in mucosal injury. Thus we hypothesized that NHE8 expression is inhibited during colitis and that SST treatment during pathological conditions can restore NHE8 expression. Our data showed for the first time that NHE8 is expressed in the human colonic tissue and that NHE8 expression is decreased in ulcerative colitis (UC) patients. We also found that octreotide could stimulate colonic NHE8 expression in colitic mice. Furthermore, the somatostatin receptor 2 (SSTR2) agonist seglitide and the somatostatin receptor 5 (SSTR5) agonist L-817,818 could restore NHE8 expression via its role in suppressing ERK1/2 phosphorylation. Our study uncovered a novel mechanism of SST stimulation of NHE8 expression in colitis.

scholarly journals NHE2X3 DKO mice exhibit gender-specific NHE8 compensation

2011 ◽  
Vol 300 (4) ◽  
pp. G647-G653 ◽  
Author(s):  
Hua Xu ◽  
Jing Li ◽  
Rongji Chen ◽  
Bo Zhang ◽  
Chunhui Wang ◽  
...  
Keyword(s):  
Sodium Absorption ◽  
Mrna Synthesis ◽  
Wild Type ◽  
Double Knockout ◽  
Sodium Hydrogen Exchanger ◽  
Wild Type Male ◽  
Wild Type Female ◽  
Important Player ◽  
First Time ◽  
Gender Specific

NHE8, the newest member of the sodium/hydrogen exchanger family, is expressed in the epithelial cells of the intestine and the kidney. Intestinal expression of NHE8 is significantly higher than that of NHE2 and NHE3 at a young age, suggesting that NHE8 is an important player for intestinal sodium absorption during early development. The current study was designed to explore if NHE8 plays a compensatory role for the loss of NHE2 and NHE3 function in NHE2X3 double-knockout (NHE2X3 DKO) mice. We further explored the regulatory mechanism(s) responsible for the change in NHE8 expression in NHE2X3 DKO mice. We found that >95% of NHE2X3 DKO mice survived through weanling. However, only 60% of male NHE2X3 DKO mice and 88% of female NHE2X3 DKO mice survived to 6 wk of life. We also found that the expression of NHE8 in wild-type female mice was higher compared with wild-type male mice after puberty. In NHE2X3 KDO mice, NHE8 expression was increased in females but not in males. Using Caco-2 cells as a model of the small intestine, we showed that testosterone inhibited endogenous NHE8 expression by reducing NHE8 mRNA synthesis, whereas estrogen had no effect on NHE8 expression. Thus our data show for the first time that intestinal NHE8 has a compensatory role in NHE2X3 DKO mice and this regulation is gender-dependent.

scholarly journals Pyk2 activation is integral to acid stimulation of sodium/hydrogen exchanger 3

2004 ◽  
Vol 114 (12) ◽  
pp. 1782-1789 ◽  
Author(s):  
Shaoying Li ◽  
Soichiro Sato ◽  
Xiaojing Yang ◽  
Patricia A. Preisig ◽  
Robert J. Alpern
Keyword(s):  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger ◽  
Stimulation Of

scholarly journals Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3

2018 ◽  
Vol 315 (5) ◽  
pp. G868-G878 ◽  
Author(s):  
Daniel R. McHugh ◽  
Calvin U. Cotton ◽  
Fraser J. Moss ◽  
Megan Vitko ◽  
Dana M. Valerio ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Mouse Models ◽  
Gastrointestinal Transit ◽  
Intestinal Lumen ◽  
Sodium Absorption ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger ◽  
Cystic Fibrosis Transmembrane

Gastrointestinal dysfunction in cystic fibrosis (CF) is a prominent source of pain among patients with CF. Linaclotide, a guanylate cyclase C (GCC) receptor agonist, is a US Food and Drug Administration-approved drug prescribed for chronic constipation but has not been widely used in CF, as the cystic fibrosis transmembrane conductance regulator (CFTR) is the main mechanism of action. However, anecdotal clinical evidence suggests that linaclotide may be effective for treating some gastrointestinal symptoms in CF. The goal of this study was to determine the effectiveness and mechanism of linaclotide in treating CF gastrointestinal disorders using CF mouse models. Intestinal transit, chloride secretion, and intestinal lumen fluidity were assessed in wild-type and CF mouse models in response to linaclotide. CFTR and sodium/hydrogen exchanger 3 (NHE3) response to linaclotide was also evaluated. Linaclotide treatment improved intestinal transit in mice carrying either F508del or null Cftr mutations but did not induce detectable Cl− secretion. Linaclotide increased fluid retention and fluidity of CF intestinal contents, suggesting inhibition of fluid absorption. Targeted inhibition of sodium absorption by the NHE3 inhibitor tenapanor produced improvements in gastrointestinal transit similar to those produced by linaclotide treatment, suggesting that inhibition of fluid absorption by linaclotide contributes to improved gastrointestinal transit in CF. Our results demonstrate that linaclotide improves gastrointestinal transit in CF mouse models by increasing luminal fluidity through inhibiting NHE3-mediated sodium absorption. Further studies are necessary to assess whether linaclotide could improve CF intestinal pathologies in patients. GCC signaling and NHE3 inhibition may be therapeutic targets for CF intestinal manifestations. NEW & NOTEWORTHY Linaclotide’s primary mechanism of action in alleviating chronic constipation is through cystic fibrosis transmembrane conductance regulator (CFTR), negating its use in patients with cystic fibrosis (CF). For the first time, our findings suggest that in the absence of CFTR, linaclotide can improve fluidity of the intestinal lumen through the inhibition of sodium/hydrogen exchanger 3. These findings suggest that linaclotide could improve CF intestinal pathologies in patients.

Mo1752 Linaclotide Induces Endocytosis of the Sodium/Hydrogen Exchanger 3 (NHE3) and Inhibits Sodium Absorption

2014 ◽  
Vol 146 (5) ◽  
pp. S-652 ◽  
Author(s):  
Nadia Ameen ◽  
Robert L. Jakab ◽  
Gerhard Hannig ◽  
Boris Tchernychev ◽  
David Arthur ◽  
...  
Keyword(s):  
Sodium Absorption ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger

scholarly journals Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors

2021 ◽  
Vol 22 (6) ◽  
pp. 2999
Author(s):  
Benjamin J. Buckley ◽  
Ashna Kumar ◽  
Ashraf Aboelela ◽  
Richard S. Bujaroski ◽  
Xiuju Li ◽  
...  
Keyword(s):  
Selectivity Ratio ◽  
Dual Targeting ◽  
Sodium Hydrogen ◽  
Type Plasminogen Activator ◽  
Single Target ◽  
Urokinase Type Plasminogen Activator ◽  
Anti Cancer ◽  
Sodium Hydrogen Exchanger ◽  
A Cell ◽  
Cell Invasiveness

The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co‑screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM; NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5,715 nM; NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition.

scholarly journals Phosphoproteomic Analysis of Two Contrasting Maize Inbred Lines Provides Insights into the Mechanism of Salt-Stress Tolerance

2019 ◽  
Vol 20 (8) ◽  
pp. 1886 ◽  
Author(s):  
Xiaoyun Zhao ◽  
Xue Bai ◽  
Caifu Jiang ◽  
Zhen Li
Keyword(s):  
Salt Stress ◽  
Inbred Line ◽  
Carbon Metabolism ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Glutathione Metabolism ◽  
Label Free ◽  
Plasma Membrane Intrinsic Protein ◽  
Sodium Hydrogen ◽  
Salt Response ◽  
Sodium Hydrogen Exchanger

Salinity is a major abiotic stress that limits maize yield and quality throughout the world. We investigated phosphoproteomics differences between a salt-tolerant inbred line (Zheng58) and a salt-sensitive inbred line (Chang7-2) in response to short-term salt stress using label-free quantitation. A total of 9448 unique phosphorylation sites from 4116 phosphoproteins in roots and shoots of Zheng58 and Chang7-2 were identified. A total of 209 and 243 differentially regulated phosphoproteins (DRPPs) in response to NaCl treatment were detected in roots and shoots, respectively. Functional analysis of these DRPPs showed that they were involved in carbon metabolism, glutathione metabolism, transport, and signal transduction. Among these phosphoproteins, the expression of 6-phosphogluconate dehydrogenase 2, pyruvate dehydrogenase, phosphoenolpyruvate carboxykinase, glutamate decarboxylase, glutamate synthase, l-gulonolactone oxidase-like, potassium channel AKT1, high-affinity potassium transporter, sodium/hydrogen exchanger, and calcium/proton exchanger CAX1-like protein were significantly regulated in roots, while phosphoenolpyruvate carboxylase 1, phosphoenolpyruvate carboxykinase, sodium/hydrogen exchanger, plasma membrane intrinsic protein 2, glutathione transferases, and abscisic acid-insensitive 5-like protein were significantly regulated in shoots. Zheng58 may activate carbon metabolism, glutathione and ascorbic acid metabolism, potassium and sodium transportation, and the accumulation of glutamate to enhance its salt tolerance. Our results help to elucidate the mechanisms of salt response in maize seedlings. They also provide a basis for further study of the mechanism underlying salt response and tolerance in maize and other crops.

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