Sodium and Potassium Balance Depends on αENaC Expression in Connecting Tubule

Christensen, Birgitte Mønster; Perrier, Romain; Wang, Qing; Zuber, Annie Mercier; Maillard, Marc; Mordasini, David; Malsure, Sumedha; Ronzaud, Caroline; Stehle, Jean-Christophe; Rossier, Bernard C.; Hummler, Edith

doi:10.1681/asn.2009101077

Cited by 86 publications

(79 citation statements)

References 31 publications

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“…The chloriuretic phenotype is evident in both the CNT/CD-specific KO mouse described here and the global KO mouse generated by Fujita et al (20). Accumulation of luminal Cl − increases the magnitude of V te , depolarizes the apical membrane, and consequently inhibits ENaC (8), causing Na + -wasting defects similar to the CNT/CDspecific ENaC KO mouse (22). The renal loss of salt and volume is compatible with the hypotensive phenotype of claudin-4 KO.…”

Section: Discussionmentioning

confidence: 63%

“…Aqp2 is expressed along the CNT and CD (SI Appendix, Fig. S3A) (21); the Aqp2 Cre transgenic mice have been successfully used to generate the CNT/CD-specific KO of ENaC (22) and mineralocorticoid receptor (23). In claudin-4 flox/flox /Aqp2 Cre mice, the claudin-4 expression in TL and DCT2 was not affected, revealed by clear colocalization with Aqp1 (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

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The Cap1–claudin-4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation

Gong

Yang³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The paracellular pathway through the tight junction provides an important route for transepithelial chloride reabsorption in the kidney, which regulates extracellular salt content and blood pressure. Defects in paracellular chloride reabsorption may in theory cause deregulation of blood pressure. However, there is no evidence to prove this theory or to demonstrate the in vivo role of the paracellular pathway in renal chloride handling. Here, using a tissue-specific KO approach, we have revealed a chloride transport pathway in the kidney that requires the tight junction molecule claudin-4. The collecting duct-specific claudin-4 KO animals developed hypotension, hypochloremia, and metabolic alkalosis due to profound renal wasting of chloride. The claudin-4-mediated chloride conductance can be regulated endogenously by a proteasechannel-activating protease 1 (cap1). Mechanistically, cap1 regulates claudin-4 intercellular interaction and membrane stability. A putative cap1 cleavage site has been identified in the second extracellular loop of claudin-4, mutation of which abolished its regulation by cap1. The cap1 effects on paracellular chloride permeation can be extended to other proteases such as trypsin, suggesting a general mechanism may also exist for proteases to regulate the tight junction permeabilities. Together, we have discovered a theory that paracellular chloride permeability is physiologically regulated and essential to renal salt homeostasis and blood pressure control.chloride channel | epithelium | hypertension C hloride is the most abundant extracellular anion and thereby determines extracellular fluid volume (ECFV) and blood pressure (BP) (1, 2). The kidney plays a vital role in ECFV and BP control through complex regulatory mechanisms acting upon ion channels and transporters located in the aldosterone-sensitive distal nephron (ASDN) (3, 4). The ASDN comprises the distal convoluted tubule (DCT), the connecting tubule (CNT), and the collecting duct (CD). The primary chloride transport mechanism in the DCT is through the thiazide-sensitive Na + /Cl − cotransporter (NCC) to reabsorb Cl − coupled with equal moles of Na + (5). The chloride transport mechanism in the CNT and CD, on the other hand, has been under debate for many years. Recent advances have identified an electroneutral transport pathway for chloride using the Cl − /bicarbonate exchanger (Slc26a4; pendrin) (6) and the Na + -driven Cl − /bicarbonate exchanger (Slc4a8; NDCBE) (7) in the β-intercalated cells (ICs) of CNT and CD. However, such an electroneutral pathway is not able to couple Cl − reabsorption with epithelial sodium channel (ENaC)-based Na + reabsorption that takes place in the principal cells (PCs) of CNT and CD (8), despite many efforts to connect ENaC and pendrin gene expression through endocrine or paracrine mechanisms (9, 10). We and others have previously demonstrated the presence of a paracellular Cl − pathway or "chloride shunt" in vitro in the CNT and CD cells (11,12). The paracellular Cl − channel is made of a key claud...

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Section: Discussionmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

The Cap1–claudin-4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation

Gong

Yang³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…24,25 Changes in sodium transport in the cortical collecting duct will affect downstream fluid delivery to the medullary portions of the Representative immunoblots and densitometric analysis of aquaporin-2 (AQP2) in renal outer and inner medulla in CD-KO and control mice at baseline (control: n ϭ 4; CD-KO: n ϭ 4) and after 18 hours of water deprivation (control: n ϭ 4; CD-KO: n ϭ 5). In water-deprived control mice, outer medullary AQP2 expression levels were significantly increased compared with baseline controls and water-deprived CD-KO mice.…”

Section: Elimination Of At 1a Receptors From Collecting Duct Does Notmentioning

confidence: 99%

AT1 Receptors in the Collecting Duct Directly Modulate the Concentration of Urine

Stegbauer

Gurley

Sparks

et al. 2011

Journal of the American Society of Nephrology

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Mice lacking AT 1 angiotensin receptors have an impaired capacity to concentrate the urine, but the underlying mechanism is unknown. To determine whether direct actions of AT 1 receptors in epithelial cells of the collecting duct regulate water reabsorption, we used Cre-Loxp technology to specifically eliminate AT 1A receptors from the collecting duct in mice (CD-KOs). Although levels of AT 1A receptor mRNA in the inner medulla of CD-KO mice were significantly reduced, their kidneys appeared structurally normal. Under basal conditions, plasma and urine osmolalities and urine volumes were similar between CD-KO mice and controls. The increase in urine osmolality in response to water deprivation or vasopressin administration, however, was consistently attenuated in CD-KO mice. Similarly, levels of aquaporin-2 protein in inner and outer medulla after water deprivation were significantly lower in CD-KO mice compared with controls, despite its normal localization to the apical membrane. In summary, these results demonstrate that AT 1A receptors in epithelial cells of the collecting duct directly modulate aquaporin-2 levels and contribute to the concentration of urine. The renin-angiotensin system (RAS) has myriad physiologic actions including the regulation of water homeostasis through modulation of thirst, vasopressin release, and urinary concentrating mechanisms. 1-5 Pharmacologic and gene targeting studies suggest that these actions are mediated primarily by type 1 (AT 1 ) receptors. 5,6 Mice have two AT 1 receptor isoforms, AT 1A and AT 1B , which are highly homologous. The AT 1A receptor is predominantly expressed in most tissues including the kidney and is the murine homologue to the single human AT 1 receptor. Mice completely lacking AT 1A receptors develop polyuria and an impaired urinary concentrating capacity, with an attenuated increase in urine osmolality after water deprivation or vasopressin administration. 5,6 On the other hand, gene targeting studies have demonstrated distinct roles for the AT 1B receptor in the regulation of thirst. 7,8 Nonetheless, the precise mechanisms and cellular targets of AT 1A receptors responsible for regulating urine concentration have not been precisely documented.Evidence from in vivo and in vitro studies suggests that the collecting duct is an important target for the modulation of water handling by the RAS. For example, in cell culture experiments, it

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“…In serving this role, ENaC plays important roles in the regulation of extracellular fluid volume and blood pressure (1,20). Of the three ENaC subunits (␣, ␤, and ␥), ␣ENaC appears to be critical to the overall salt balance, as evidenced by the finding that mice with targeted inactivation of ␣ENaC in the connecting tubule (CNT)/collecting duct (CD) exhibit severe renal salt wasting characteristic of a pseudohypoaldosteronism type I phenotype (5). ␣ENaC is also a molecular target of aldosterone, which stimulates its transcription in a manner that is rate limiting for the full induction of ENaC activity in the CD in animal models.…”

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confidence: 99%

“…A promoter-reporter study (11) of the ␣ENaC gene in CD cells revealed the involvement of a glucocorticoid responsive element at Ϫ811 in the aldosterone response, leading to the assumption that aldosterone activation of ␣ENaC gene transcription was solely due to the action of aldosterone, liganded to the mineralocorticoid receptor (MR), acting at this glucocorticoid responsive element. However, mice with CNT/CDspecific MR inactivation (19) failed to develop the severe salt-wasting phenotype observed with CNT/CD-specific ablation of ␣ENaC in these same segments (5), indicating the large contribution of MR-independent pathways in ␣ENaC gene regulation.…”

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confidence: 99%

Aldosterone reprograms promoter methylation to regulate αENaC transcription in the collecting cuct

Kong

Kone

2013

American Journal of Physiology-Renal Physiology

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Yu Z, Kong Q, Kone BC. Aldosterone reprograms promoter methylation to regulate ␣ENaC transcription in the collecting cuct. Am J Physiol Renal Physiol 305: F1006 -F1013, 2013. First published August 7, 2013 doi:10.1152/ajprenal.00407.2013.-Aldosterone increases tubular Na ϩ absorption largely by increasing ␣-epithelial Na ϩ channel (␣ENaC) transcription in collecting duct principal cells. How aldosterone reprograms basal ␣ENaC transcription to high-level activity in the collecting duct is incompletely understood. Promoter methylation, a covalent but reversible epigenetic process, has been implicated in the control of gene expression in health and disease. We investigated the role of promoter methylation/demethylation in the epigenetic control of basal and aldosterone-stimulated ␣ENaC transcription in mIMCD3 collecting duct cells. Bisulfite treatment and sequencing analysis after treatment of the cells with the DNA methyltransferase (DNMT) inhibitor 5-aza-2=-deoxycytidine (5-Aza-CdR) identified clusters of methylated cytosines in a CpG island near the transcription start site of the ␣ENaC promoter. 5-Aza-CdR treatment or small interfering RNA-mediated knockdown of DNMT3b or methyl-CpG-binding domain protein (MBD)-4 derepressed basal ␣ENaC transcription, indicating that promoter methylation suppresses basal ␣ENaC transcription. Aldosterone triggered a time-dependent decrease in 5mC and DNMT3b and a concurrent enrichment in 5-hydroxymethylcytosine (5hmC) and ten-eleven translocation (Tet)2 at the ␣ENaC promoter, consistent with active demethylation. 5-AzaCdR mimicked aldosterone by enhancing Sp1 binding to the ␣ENaC promoter. We conclude that DNMT3b-and MBD4-dependent methylation of the ␣ENaC promoter limits basal ␣ENaC transcription, in part by limiting Sp1 binding and trans-activation. Aldosterone stimulates the dispersal of DNMT3b and recruitment of Tet2 to demethylate the ␣ENaC promoter to induce ␣ENaC transcription. These results disclose a novel epigenetic mechanism for the control of basal and aldosterone-induced ␣ENaC transcription that adds to previously described epigenetic controls exerted by histone modifications. epigenetic; chromatin; transcription factor; methylcytosine; methyltransferase; epithelial Na ϩ channel THE EPITHELIAL NA ϩ CHANNEL (ENaC) mediates Na ϩ entry across the apical membranes of salt-absorbing epithelia of the kidney, distal colon, and lung and functions as the rate-limiting step in active transepithelial Na ϩ and fluid absorption. In serving this role, ENaC plays important roles in the regulation of extracellular fluid volume and blood pressure (1,20). Of the three ENaC subunits (␣, ␤, and ␥), ␣ENaC appears to be critical to the overall salt balance, as evidenced by the finding that mice with targeted inactivation of ␣ENaC in the connecting tubule (CNT)/collecting duct (CD) exhibit severe renal salt wasting characteristic of a pseudohypoaldosteronism type I phenotype (5). ␣ENaC is also a molecular target of aldosterone, which stimulates its transcription in a manner that is rate l...

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Sodium and Potassium Balance Depends on αENaC Expression in Connecting Tubule

Cited by 86 publications

References 31 publications

The Cap1–claudin-4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation

The Cap1–claudin-4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation

AT1 Receptors in the Collecting Duct Directly Modulate the Concentration of Urine

Aldosterone reprograms promoter methylation to regulate αENaC transcription in the collecting cuct

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