Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney-specific isoform of WNK1 and prevents hypertension

Hadchouel, Juliette; Soukaseum, Christelle; Büsst, Cara; Zhou, Xiaoou; Baudrie, Véronique; Zürrer, Tany; Cambillau, Michèle; Elghozi, Jean‐Luc; Lifton, Richard P.; Loffing, Johannes; Jeunemaı̂tre, Xavier

doi:10.1073/pnas.1006128107

Cited by 98 publications

(97 citation statements)

References 33 publications

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“…The telemetry analysis has provided preliminary support to the circadian regulation hypothesis. Notably, several KO models in the WNK1-SPAK/OSR1 pathway have demonstrated similar circadian rhythm-dependent BP phenotypes (38,39). The circadian clock genes (Cryptochrome-1 and -2) control aldosterone biosynthesis levels that oscillate by about fourfold during the day-night cycle (40).…”

Section: Discussionmentioning

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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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: 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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“…Hadchouel et al reported that BKa protein abundance along with ROMK is upregulated in KS-WNK1 KO mice, 49 suggesting that KS-WNK1 regulates BK channel activity. However,Cheng et al also reported that BK channel-mediated K secretion is not significantly affected during HK diet feeding in KS-WNK1 knockout mice.…”

Section: Hek Bka Cells Were Transfected With a Series Of Doses Of Wnkmentioning

confidence: 99%

“…50 Whether knockout of KS-WNK1 affects WNK1 kinase activity or WNK1 expression level, which could contribute to the increased BK protein abundance, remains to be further elucidated. 49,50 Since WNK1 expression is upregulated in patients with PHA-II, 1 inhibition of ROMK by WNK1 could explain the clinical phenotype of hyperkalemia. 45 However, it is still to be determined whether the ratio of WNK1 over KS-WNK1 is crucial in directly modulating BK channel activity.…”

Section: Hek Bka Cells Were Transfected With a Series Of Doses Of Wnkmentioning

confidence: 99%

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

Liu

Song

Shi

et al. 2015

Journal of the American Society of Nephrology

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With no lysine (WNK) kinases are members of the serine/threonine kinase family. We previously showed that WNK4 inhibits renal large-conductance Ca 2+ -activated K + (BK) channel activity by enhancing its degradation through a lysosomal pathway. In this study, we investigated the effect of WNK1 on BK channel activity. In HEK293 cells stably expressing the a subunit of BK (HEK-BKa cells), siRNA-mediated knockdown of WNK1 expression significantly inhibited both BKa channel activity and open probability. Knockdown of WNK1 expression also significantly inhibited BKa protein expression and increased ERK1/2 phosphorylation, whereas overexpression of WNK1 significantly enhanced BKa expression and decreased ERK1/2 phosphorylation in a dose-dependent manner in HEK293 cells. Knockdown of ERK1/2 prevented WNK1 siRNA-mediated inhibition of BKa expression. Similarly, pretreatment of HEK-BKa cells with the lysosomal inhibitor bafilomycin A1 reversed the inhibitory effects of WNK1 siRNA on BKa expression in a dose-dependent manner. Knockdown of WNK1 expression also increased the ubiquitination of BKa channels. Notably, mice fed a high-K + diet for 10 days had significantly higher renal protein expression levels of BKa and WNK1 and lower levels of ERK1/2 phosphorylation compared with mice fed a normal-K + diet. These data suggest that WNK1 enhances BK channel function by reducing ERK1/2 signaling-mediated lysosomal degradation of the channel. With no lysine (WNK) kinase belongs to a family of serine/threonine kinases. Mutations of WNK1 and WNK4 are responsible for pseudohypoaldosteronism type II (PHAІІ), characterized by hypertension, hyperkalemia, and metabolic acidosis. 1,2 The disease mutation in WNK1 or WNK4 kinase resulting in hyperkalemia suggests a role of WNK in potassium handling in renal distal nephron, which contains two major potassium channels, renal outer medullary K + channels (ROMK) and Big K (BK) channels. 3,4 WNK4 inhibits ROMK channel activity and its surface expression, whereas WNK4 disease mutant enhances its inhibitory effect on ROMK. 5 WNK1 also inhibits ROMK activity; however, a kidney-specific form of WNK1 (KS-WNK1) reverses WNK1's effect on ROMK. 6 WNK4 inhibits BK channel activity and protein expression, 7-9 whereas WNK4 disease mutant also enhances its inhibitory effect on BK activity via a ubiquitin-dependent pathway. 9 BK channel (or Maxi K) is a large conductance Ca 2+ and voltage-activated K channel. 10 BK is encoded by the gene slo1 11 and is widely distributed in many different

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“…Similarly, increasing NCC activity by inactivating KS-WNK1 was also not sufficient to cause hyperkalemic hypertension, because it was associated with a compensatory decrease in ENaC [38]. Instead, familial hyperkalemic hypertension is caused by mutations in the genes encoding WNK1, WNK4, Kelch-like 3 or Cullin-3, which result in overactivity of NCC (Table 2) [7,68,131].…”

Section: Familial Hyperkalemic Hypertensionmentioning

confidence: 99%

“…Although this review focused on NCC, sodium excretion by the kidney depends on many other sodium transporters, including NHE3, NKCC2, ENaC, and pendrin. Stimuli that activate NCC, sometimes also activate these other transporters, but an opposite, compensatory response may also occur [38,84,99]. In conclusion, the role of NCC in normal physiology and in the pathophysiology of hypertension is expanding and will 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 20 likely continue to do so in coming years.…”

Section: Perspectivesmentioning

confidence: 99%

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Moes

Lubbe

Zietse

et al. 2013

Pflugers Arch - Eur J Physiol

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SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10 % of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.

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Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney-specific isoform of WNK1 and prevents hypertension

Cited by 98 publications

References 33 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

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

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