Effect of Cytosolic pH on Epithelial Na+ Channel in Normal and Cystic Fibrosis Sweat Ducts

Reddy, M. M.; Wang, X. F.; Quinton, Paul M.

doi:10.1007/s00232-008-9126-4

Cited by 20 publications

(12 citation statements)

References 44 publications

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“…The lumennegative transepithelial potential is most likely generated by a combination of K ϩ channels expressed in the basolateral membrane and Na ϩ and Cl Ϫ channels expressed in the apical membrane (9,10,36). A possible cause for the reduced transepithelial potential in mice lacking pendrin is an inhibition of the apical Na ϩ channels or the basolateral K ϩ channels by an acidic cytosolic pH (47). Whether the more acidic pH in the follicular lumen is associated with a more acidic cytosolic pH, however, is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/pendrin expression

Wangemann

Kim

Billings

et al. 2009

American Journal of Physiology-Renal Physiology

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Section: Discussionmentioning

confidence: 99%

Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/pendrin expression

Wangemann

Kim

Billings

et al. 2009

American Journal of Physiology-Renal Physiology

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“…39,[46][47][48] Also, the in vivo activity of ENaC, the lithium entry site of principal cells, has been reported to be functionally paired with CA activity, because CA inhibition by acetazolamide reduced the intracellular pH and ENaC activity in sweat duct cells and colon. 49,50 However, mpkCCD cells may not fully represent principal cells, and because intercalated cells express abundant levels of CA2, -4, 52,53 it has been suggested that acidosis-induced proliferation of a-intercalated cells may contribute to Li-NDI. 16 It is unlikely, however, that attenuation of Li-NDI in our mice is caused by direct action of acetazolamide on a-intercalated cells or collecting duct remodeling for several reasons.…”

Section: Discussionmentioning

confidence: 99%

Acetazolamide Attenuates Lithium–Induced Nephrogenic Diabetes Insipidus

Groot¹,

Sinke²,

Kortenoeven³

et al. 2015

JASN

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To reduce lithium-induced nephrogenic diabetes insipidus (lithium-NDI), patients with bipolar disorder are treated with thiazide and amiloride, which are thought to induce antidiuresis by a compensatory increase in prourine uptake in proximal tubules. However, thiazides induced antidiuresis and alkalinized the urine in lithium-NDI mice lacking the sodium-chloride cotransporter, suggesting that inhibition of carbonic anhydrases (CAs) confers the beneficial thiazide effect. Therefore, we tested the effect of the CA-specific blocker acetazolamide in lithium-NDI. In collecting duct (mpkCCD) cells, acetazolamide reduced the cellular lithium content and attenuated lithium-induced downregulation of aquaporin-2 through a mechanism different from that of amiloride. Treatment of lithium-NDI mice with acetazolamide or thiazide/amiloride induced similar antidiuresis and increased urine osmolality and aquaporin-2 abundance. Thiazide/amiloride-treated mice showed hyponatremia, hyperkalemia, hypercalcemia, metabolic acidosis, and increased serum lithium concentrations, adverse effects previously observed in patients but not in acetazolamide-treated mice in this study. Furthermore, acetazolamide treatment reduced inulin clearance and cortical expression of sodium/hydrogen exchanger 3 and attenuated the increased expression of urinary PGE2 observed in lithium-NDI mice. These results show that the antidiuresis with acetazolamide was partially caused by a tubular-glomerular feedback response and reduced GFR. The tubular-glomerular feedback response and/or direct effect on collecting duct principal or intercalated cells may underlie the reduced urinary PGE2 levels with acetazolamide, thereby contributing to the attenuation of lithium-NDI. In conclusion, CA activity contributes to lithium-NDI development, and acetazolamide attenuates lithium-NDI development in mice similar to thiazide/amiloride but with fewer adverse effects.

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“…An important next step would be to explore the effects of modeling the pH along the duct. We expect pH to have an effect on bicarbonate due to buffering, but pH may also affect the membrane potential and the sodium concentration through the ENaC channel (42).…”

Section: Discussionmentioning

confidence: 99%

A quantitative analysis of electrolyte exchange in the salivary duct

Patterson

Catalán

Melvin

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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for K ϩ and HCO 3 Ϫ , producing a hypotonic final saliva with no apparent loss in volume. We have developed a tool that aims to understand how the ducts achieve this electrolyte exchange while maintaining the same volume. This tool is part of a larger multiscale model of the salivary gland and can be used at the duct or gland level to investigate the effects of genetic and chemical alterations. In this study, we construct a radially symmetric mathematical model of the mouse salivary gland duct, representing the lumen, the cell, and the interstitium. For a given flow and primary saliva composition, we predict the potential differences and the luminal and cytosolic concentrations along a duct. Our model accounts well for experimental data obtained in wild-type animals as well as knockouts and chemical inhibitors. Additionally, the luminal membrane potential of the duct cells is predicted to be very depolarized compared with acinar cells. We investigate the effects of an electrogenic vs. electroneutral anion exchanger in the luminal membrane on concentration and the potential difference across the luminal membrane as well as how impairing the cystic fibrosis transmembrane conductance regulator channel affects other ion transporting mechanisms. Our model suggests the electrogenicity of the anion exchanger has little effect in the submandibular duct. salivary glands; tubular transport; membrane transport SALIVA IS COMPOSED OF 99% water, and yet that other 1% helps to maintain oral health by providing an appropriate ecological balance in the mouth (45). The basic secretory unit of a salivary gland consists of a cluster of acinar cells and a segment of duct (Fig. 1). The acinar cells secrete an isotonic primary saliva high in Na ϩ and Cl Ϫ but low in K ϩ . These cells produce all of the water found in saliva as the duct is considered to be highly impermeable to water (21). As the fluid travels along the duct, the duct cells exchange Na ϩ and Cl Ϫ for K ϩ and HCO 3 Ϫ , producing a hypotonic final saliva. This electrolyte exchange creates a final saliva that acts as a buffer in the mouth, neutralizing acids and inhibiting caries progression. This hypotonicity also enhances the ability to taste salty foods and nutrient-rich foods (18). Primary saliva production has been modeled by Gin et al. (16) and Palk et al. (37); however, these models do not include any representation of the salivary duct. One aim in studying this system is to provide a quantitative understanding of how hypotonicity is achieved in the mouse submandibular gland duct with no apparent change in saliva volume. It is, to the best of our knowledge, the first quantitative description of a salivary duct and is validated against a variety of experimental data. This model is also a tool that can be used alone or incorporated into a multi-scale model of the salivary gland, spanning from molecular to the tissue level (31,37,47). Depending on the application, either tool can be used to study genetic and chemical alterations, including, but not limited to, sal...

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Effect of Cytosolic pH on Epithelial Na+ Channel in Normal and Cystic Fibrosis Sweat Ducts

Cited by 20 publications

References 44 publications

Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/pendrin expression

Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/pendrin expression

Acetazolamide Attenuates Lithium–Induced Nephrogenic Diabetes Insipidus

A quantitative analysis of electrolyte exchange in the salivary duct

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