Molecular mechanisms of epithelial cell-specific expression and regulation of the human anion exchanger (pendrin) gene

Adler, Lior; Efrati, Edna; Zelikovic, Israel

doi:10.1152/ajpcell.00486.2007

Cited by 37 publications

(51 citation statements)

References 59 publications

(97 reference statements)

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“…The strong reduction in pendrin expression, as well as its internalization observed in the B-intercalated cells of K + -depleted mice might be due to a fall in intracellular pH as a result of an increased exchange of K + out of the cell for H + into the cell. In line with these observations, previous studies showed that acidic pH decreases, whereas alkaline pH increases pendrin promoter activity in HEK293 cells [55]. Together, these observations support the concept that cellular acidosis leads to pendrin down-regulation that, in turn, participates in determining metabolic alkalosis in the setting of the chronic K + depletion.…”

Section: Discussionsupporting

confidence: 87%

Co-Regulated Pendrin and Aquaporin 5 Expression and Trafficking in Type-B Intercalated Cells under Potassium Depletion

Procino

Milano

Tamma

et al. 2013

Cell Physiol Biochem

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Background: We recently reported that aquaporin 5 (AQP5), a water channel never identified in the kidney before, co-localizes with pendrin at the apical membrane of type-B intercalated cells in the kidney cortex. Since co-expression of AQP5 and pendrin in the apical membrane domain is a common feature of several other epithelia such as cochlear and bronchial epithelial cells, we evaluated here whether this strict membrane association may reflect a co-regulation of the two proteins. To investigate this possibility, we analyzed AQP5 and pendrin expression and trafficking in mice under chronic K⁺ depletion, a condition that results in an increased ability of renal tubule to reabsorb bicarbonate, often leads to metabolic alkalosis and is known to strongly reduce pendrin expression. Methods: Mice were housed in metabolic cages and pair-fed with either a standard laboratory chow or a K⁺-deficient diet. AQP5 abundance was assessed by western blot in whole kidney homogenates and AQP5 and pendrin were localized by confocal microscopy in kidney sections from those mice. In addition, the short-term effect of changes in external pH on pendrin trafficking was evaluated by fluorescence resonance energy transfer (FRET) in MDCK cells, and the functional activity of pendrin was tested in the presence and absence of AQP5 in HEK 293 Phoenix cells. Results: Chronic K⁺ depletion caused a strong reduction in pendrin and AQP5 expression. Moreover, both proteins shifted from the apical cell membrane to an intracellular compartment. An acute pH shift from 7.4 to 7.0 caused pendrin internalization from the plasma membrane. Conversely, a pH shift from 7.4 to 7.8 caused a significant increase in the cell surface expression of pendrin. Finally, pendrin ion transport activity was not affected by co-expression with AQP5. Conclusions: The co-regulation of pendrin and AQP5 membrane expression under chronic K⁺-deficiency indicates that these two molecules could cooperate as an osmosensor to rapidly detect and respond to alterations in luminal fluid osmolality.

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Section: Discussionsupporting

confidence: 87%

Co-Regulated Pendrin and Aquaporin 5 Expression and Trafficking in Type-B Intercalated Cells under Potassium Depletion

Procino

Milano

Tamma

et al. 2013

Cell Physiol Biochem

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“…Therefore, it was not surprising to observe coordinated regulation of AE4 and pendrin in response to acidosis and alkalosis. Indeed, Foxi1 directly activates the AE4 promoter in vitro (14); in addition, low pH decreases and high pH increases human pendrin gene expression in transfected kidney cells (1). Acid loading for 24 -48 h causes a reduction in pendrin protein expression in the mouse kidney along with a shift of expression from the apical membrane to the cytosol (33), and these changes were reversed with alkali loading (33).…”

Section: Discussionmentioning

confidence: 99%

Insights into acidosis-induced regulation of SLC26A4 (pendrin) and SLC4A9 (AE4) transporters using three-dimensional morphometric analysis of β-intercalated cells

Purkerson

Heintz

Nakamori

et al. 2014

American Journal of Physiology-Renal Physiology

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Purkerson JM, Heintz EV, Nakamori A, Schwartz GJ. Insights into acidosis-induced regulation of SLC26A4 (pendrin) and SLC4A9 (AE4) transporters using three-dimensional morphometric analysis of ␤-intercalated cells. Am J Physiol Renal Physiol 307: F601-F611, 2014. First published July 2, 2014; doi:10.1152/ajprenal.00404.2013.-The purpose of this study was to examine the three-dimensional (3-D) expression and distribution of anion transporters pendrin (SLC26A4) and anion exchanger (AE)4 (SLC4A9) in ␤-intercalated cells (␤-ICs) of the rabbit cortical collecting duct (CCD) to better characterize the adaptation to acid-base disturbances. Confocal analysis and 3-D reconstruction of ␤-ICs, using identifiers of the nucleus and zona occludens, permitted the specific orientation of cells from normal, acidotic, and recovering rabbits, so that adaptive changes could be quantified and compared. The pendrin cap likely mediates apical Cl Ϫ /HCO 3 Ϫ exchange, but it was also found beneath the zona occludens and in early endosomes, some of which may recycle back to the apical membrane via Rab11a ϩ vesicles. Acidosis reduced the size of the pendrin cap, observed as a large decrease in cap volume above and below the zona occludens, and the volume of the Rab11a ϩ apical recycling compartment. Correction of the acidosis over 12-18 h reversed these changes. Consistent with its proposed function in the basolateral exit of Na ϩ via Na ϩ -HCO 3 Ϫ cotransport, AE4 was expressed as a barrel-like structure in the lateral membrane of ␤-ICs. Acidosis reduced AE4 expression in ␤-ICs, but this was rapidly reversed during the recovery from acidosis. The coordinate regulation of pendrin and AE4 during acidosis and recovery is likely to affect the magnitude of acid-base and possibly Na ϩ transport across the CCD. In conclusion, acidosis induces a downregulation of AE expression in ␤-ICs and a diminished presence of pendrin in apical recycling endosomes. acidosis; alkalosis; anion exchangers; anion exchanger 4; confocal microscopy; rabbit FINAL REGULATION of acid-base transport occurs in the distal nephron of the kidney, particularly in the cortical collecting duct (CCD). We have previously shown in rabbits that acidosis results in increased proton secretion and decreased HCO 3 Ϫ secretion, respectively, by ␣-and ␤-intercalated cells (ICs) from isolated perfused CCDs (23,25,26,29). Some of these adaptive changes occur via a downregulation of the apical Cl Ϫ /HCO 3 Ϫ exchanger, which mediates HCO 3 Ϫ secretion (17,26). This exchanger in ␤-ICs was subsequently shown to be pendrin (SLC26A4) (22); it appears as an apical cap and clearly plays a role in acid-base regulation. However, other studies have shown that pendrin expression is also dependent on urinary Cl Ϫ excretion (11, 34) and, if unregulated, could cause hypertension (34). A study (21) of pendrin expression during acid-base disturbances revealed that the expression, mRNA, protein abundance, and number of pendrin-positive cells in rabbit kidneys were decreased after 3 days of acidosis. Simila...

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“…Enhanced luminal pendrin localization was observed in animals loaded with bicarbonate (203), given DOCA (196), or during chloride depletion (197), whereas several treatments altered total pendrin abundance in the kidney (57,67,139,192,203). Studies in various cell lines provided evidence for direct regulatory domains in the promoter region sensitive to intracellular pH and possibly to aldosterone (1). A fourth and indirect means of regulation may be changes in the number of pendrin expressing non-type A intercalated cells as observed in states of chronic metabolic acidosis or altered distal chloride delivery associated with a changed relative abundance of pendrin positive cells (67,192,203).…”

Section: Ae1mentioning

confidence: 99%

Regulated acid–base transport in the collecting duct

Wagner

Devuyst

Bourgeois

et al. 2009

Pflugers Arch - Eur J Physiol

161

142

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The renal collecting system serves the fine-tuning of renal acid-base secretion. Acid-secretory type-A intercalated cells secrete protons via a luminally expressed V-type H(+)-ATPase and generate new bicarbonate released by basolateral chloride/bicarbonate exchangers including the AE1 anion exchanger. Efficient proton secretion depends both on the presence of titratable acids (mainly phosphate) and the concomitant secretion of ammonia being titrated to ammonium. Collecting duct ammonium excretion requires the Rhesus protein RhCG as indicated by recent KO studies. Urinary acid secretion by type-A intercalated cells is strongly regulated by various factors among them acid-base status, angiotensin II and aldosterone, and the Calcium-sensing receptor. Moreover, urinary acidification by H(+)-ATPases is modulated indirectly by the activity of the epithelial sodium channel ENaC. Bicarbonate secretion is achieved by non-type-A intercalated cells characterized by the luminal expression of the chloride/bicarbonate exchanger pendrin. Pendrin activity is driven by H(+)-ATPases and may serve both bicarbonate excretion and chloride reabsorption. The activity and expression of pendrin is regulated by different factors including acid-base status, chloride delivery, and angiotensin II and may play a role in NaCl retention and blood pressure regulation. Finally, the relative abundance of type-A and non-type-A intercalated cells may be tightly regulated. Dysregulation of intercalated cell function or abundance causes various syndromes of distal renal tubular acidosis underlining the importance of these processes for acid-base homeostasis.

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Molecular mechanisms of epithelial cell-specific expression and regulation of the human anion exchanger (pendrin) gene

Cited by 37 publications

References 59 publications

Co-Regulated Pendrin and Aquaporin 5 Expression and Trafficking in Type-B Intercalated Cells under Potassium Depletion

Co-Regulated Pendrin and Aquaporin 5 Expression and Trafficking in Type-B Intercalated Cells under Potassium Depletion

Insights into acidosis-induced regulation of SLC26A4 (pendrin) and SLC4A9 (AE4) transporters using three-dimensional morphometric analysis of β-intercalated cells

Regulated acid–base transport in the collecting duct

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