The recycling regulation of sodium-hydrogen exchanger isoform 3(NHE3) in epithelial cells

The proximal duodenum is exposed to extreme elevations of Pco2because of the continuous mixture of secreted HCO3−with gastric acid. These elevations (up to 80 kPa) are likely to place the mucosal cells under severe acid stress. Furthermore, we hypothesized that, unlike most other cells, the principal source of CO2for duodenal epithelial cells is from the lumen. We hence examined the effect of elevated luminal Pco2on duodenal HCO3−secretion (DBS) in the rat. DBS was measured by the pH-stat method. For CO2challenge, the duodenum was superfused with a high Pco2solution. Intracellular pH (pHi) of duodenal epithelial cells was measured by ratio microfluorometry. CO2challenge, but not isohydric solutions, strongly increased DBS to approximately two times basal for up to 1 h. Preperfusion of the membrane-permeant carbonic anhydrase inhibitor methazolamide, or continuous exposure with indomethacin, fully inhibited CO2-augmented DBS. Dimethyl amiloride (0.1 mM), an inhibitor of the basolateral sodium-hydrogen exchanger 1, also inhibited CO2-augumented DBS, although S-3226, a specific inhibitor of apical sodium-hydrogen exchanger 3, did not. DIDS, an inhibitor of basolateral sodium-HCO3−cotransporter, also inhibited CO2-augemented DBS, as did the anion channel inhibitor 5-nitro-2-(3-phenylpropylamino) benzoic acid. CO2decreased epithelial cell pHi, followed by an overshoot after removal of the CO2solution. We conclude that luminal CO2diffused in the duodenal epithelial cells and was converted to H+and HCO3−by carbonic anhydrase. H+initially exited the cell, followed by secretion of HCO3−. Secretion was dependent on a functioning basolateral sodium/proton exchanger, a functioning basolateral HCO3−uptake mechanism, and submucosal prostaglandin generation and facilitated hydration of CO2into HCO3−and H+.

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984: The Sodium/Hydrogen Exchanger 1 Protein in the Bladder Cancer Response to Cisplatin Treatment

The Journal of Urology ◽

10.1016/s0022-5347(18)38221-1 ◽

2004 ◽

Vol 171 (4S) ◽

pp. 260-261

Author(s):

Benjamin E. Deverman ◽

Steven J. Weintraub

Keyword(s):

Bladder Cancer ◽

Sodium Hydrogen ◽

Sodium Hydrogen Exchanger

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Faculty Opinions recommendation of Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725239706.793501739 ◽

2014 ◽

Author(s):

Jeff Kraut

Keyword(s):

Vascular Calcification ◽

Phosphorus Absorption ◽

Sodium Hydrogen ◽

Sodium Hydrogen Exchanger

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

International Journal of Molecular Sciences ◽

10.3390/ijms22062999 ◽

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms20081886 ◽

2019 ◽

Vol 20 (8) ◽

pp. 1886 ◽

Cited By ~ 7

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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Mineralocorticoid Action and Sodium-Hydrogen Exchange: Studies in Experimental Cardiac Fibrosis

Endocrinology ◽

10.1210/en.2003-0039 ◽

2003 ◽

Vol 144 (9) ◽

pp. 3848-3851 ◽

Cited By ~ 34

Author(s):

Morag Young ◽

John Funder

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Hydrogen Exchange ◽

Cardiac Fibrosis ◽

Inflammatory Cell ◽

Mineralocorticoid Receptor Antagonist ◽

Sodium Hydrogen ◽

Sodium Hydrogen Exchanger ◽

Coronary Vasculitis ◽

Potassium Canrenoate

Abstract There is increasing evidence that the trigger for cardiac fibrosis in response to mineralocorticoid/salt administration is coronary vasculitis and that effects can be seen within days of deoxycorticosterone acetate (DOCA) administration. Furthermore, rapid, nongenomic mineralocorticoid effects on the sodium-hydrogen exchanger (NHE-1) in vascular smooth muscle cells have recently been described. That this mechanism may act as an inflammatory or profibrotic signal was tested by comparing the specific NHE-1 antagonist cariporide and the mineralocorticoid receptor antagonist K canrenoate in the rat model of mineralocorticoid/salt perivascular fibrosis over 8 d of DOCA/salt administration. Interstitial collagen, inflammatory cell infiltration, and inflammatory markers were determined. DOCA elevated blood pressure above control, cariporide +DOCA, or K canrenoate +DOCA rats, without cardiac hypertrophy. At 8 d interstitial collagen was significantly elevated in the DOCA-alone group, with levels in cariporide- and K canrenoate-treated rats not different from control. Expression of osteopontin, cyclooxygenase-2, and ED-1 were elevated by DOCA treatment, blocked by potassium canrenoate, and (for ED-1 and osteopontin) partially reduced by cariporide. These results suggest mineralocorticoid/salt-induced cardiac fibrosis may involve coronary vascular smooth muscle cell NHE-1 activity as a possible contributor to the cascade of transcriptional events that produce the characteristic coronary vasculitis seen with excess mineralocorticoid and salt.

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