Home Current issue Ahead of print Search About us Editorial board Archives Submit article Instructions Subscribe Contacts Login 
  • Users Online: 38
  • Home
  • Print this page
  • Email this page

 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 4  |  Issue : 3  |  Page : 75-80

Sodium-chloride cotransporter activity regulated by extracellular potassium


Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

Date of Web Publication28-Sep-2017

Correspondence Address:
Chong Zhang
Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Shi
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jina.jina_13_17

Rights and Permissions
  Abstract 


The thiazide-sensitive sodium-chloride cotransporter (NCC) is exclusively expressed in the apical membrane of the renal distal convoluted tubule (DCT), and it is important for maintaining fluid and salt balance. NCC is responsible for electroneutral NaCl reabsorption, and its activity is determined by phosphorylation, which was reported to be regulated by WNK-stimulated Ste20-type kinases, Ste20-related proline alanine-rich kinase, and oxidative stress response 1 kinase. WNK kinases have chloride-binding sites, and WNK4 has the highest sensitivity to intracellular chloride concentration ([Cl]i) compared with WNK1 and WNK3. NCC dysfunction often comes together with abnormal urinary potassium excretion, which is not only highlighted by Mendelian disorders such as familial hyperkalemic hypertension (FHHt) and Gitelman syndrome but also presented more frequently by long-term usage of thiazides, specific inhibitors of NCC. Recent studies have shown that extracellular potassium (K+) can modulate DCT cell membrane voltage and in turn intracellular Cl, which regulates phosphorylation of WNK kinases. Additional Cl independent mechanisms were also reported by several groups. This paper is a brief review of the recent discoveries on mechanisms of NCC regulation by extracellular potassium.

Keywords: Chloride, extracellular potassium, sodium-chloride cotransporter, WNK kinases


How to cite this article:
Ying S, Yang Y, Zhang C. Sodium-chloride cotransporter activity regulated by extracellular potassium. J Integr Nephrol Androl 2017;4:75-80

How to cite this URL:
Ying S, Yang Y, Zhang C. Sodium-chloride cotransporter activity regulated by extracellular potassium. J Integr Nephrol Androl [serial online] 2017 [cited 2017 Dec 11];4:75-80. Available from: http://www.journal-ina.com/text.asp?2017/4/3/75/215737


  Introduction Top


The distal convoluted tubule (DCT) plays a pivotal role in maintaining fluid and salt balance, which reabsorbs 5%–10% of the salt filtered by the glomerulus every day. The DCT is divided into two functionally distinct segments: the proximal portion of the DCT (DCT1) and the remote one (DCT2). Sodium-chloride cotransporter (NCC), which is crucial for blood pressure regulation and electrolyte balance, is primarily located in the DCT1 and reabsorbs Na + and Cl in an electroneutral manner while electrogenic sodium channel, the epithelial sodium channel (ENaC), is expressed from DCT2 to latter parts of distal tubule.[1] The renal outer medullary potassium channel (ROMK) is expressed along the entire distal nephron from the thick ascending limb through the collecting ducts (CDs). NCC is not directly involved in the transportation or excretion of K +; however, it is interesting that NCC dysregulation is almost always accompanied by hyperkalemia or hypokalemia. Abnormal NCC activities result from genetic disorders such as Gitelman syndrome, EAST/SeSAME syndrome, and familial hyperkalemic hypertension (FHHt) (also known as Gordon syndrome or pseudohypoaldosteronism type II), present excessive or diminished urinary potassium excretion, respectively. Gitelman syndrome is due to inactivating mutations in SLC12A3 which encodes NCC, featuring hypotension, hypokalemia, metabolic alkalosis, and hypocalcemia.[2] Loss-of-function mutations of Kcnj10 cause EAST/SeSAME syndrome in humans which is also relevant to decreased NCC function (see below for details). The patients of EAST/SeSAME syndrome usually suffer from epilepsy, ataxia, sensorineural deafness, and other complex neurological symptoms in addition to hypokalemia and metabolic alkalosis caused by the renal tubule damage similar to Gitelman syndrome.[3],[4] In contrast, overactivation of the NCC in FHHt results in hypertension, hyperkalemia, metabolic acidosis, and hypercalcemia. Therefore, one can hypothesize that activation of NCC can lead to potassium retention; NCC inactivation is to promote potassium excretion. NCC is not only supposed to regulate the excretion of K + but also its activity is regulated by serum or extracellular K +, which is reflected in the scenarios of NCC rapid dephosphorylation after high potassium diet (HK) and NCC phosphorylation after the low potassium diet (LK). It appears that NCC serves as an extracellular K + sensor. When the extracellular K + concentration ([K +]ex) is high, NCC is suppressed. Contrarily, when the [K +]ex is low, the opposite occurs. The activity of NCC is proposed to be the determinant of downstream tubule K + excretion. When NCC is inhibited, more Na + is transported to aldosterone-sensitive distal nephron (comprising the connecting tubule and CD and in some species, the DCT2), which facilitate electrogenic absorption by ENaC and K + excretion by the coupled ROMK. This review aims to summarize the latest advances in the regulation of NCC activity by extracellular K +.


  WNK-Ste20-Related Proline Alanine-Rich Kinase/oxidative Stress Response 1 Kinase-Sodium-Chloride Cotransporter Phosphorylation Cascade Top


NCC is regulated by phosphorylation at conserved threonine and serine residues in the amino-terminal domain.[5],[6] Ste20-related proline alanine-rich kinase (SPAK) and oxidative stress response 1 kinase (OSR1) which are phosphorylated by WNK kinases can phosphorylate NCC directly.[6],[7]

The WNK kinases are a family of four evolutionarily conserved serine-threonine kinases, WNK1 to WNK4, which was nominated for its lack of lysine in the second subunit of the kinase domain that is crucial for binding ATP. WNK1, WNK3, and WNK4, but not WNK2, are expressed in the kidney. Up to date, four mutated genes have been implicated in FHHt: two coding for kinases (WNK1 and WNK4) and the other two coding for ubiquitinylases (the cullin RING ligases family members kelch-like 3 [KLHL3] and cullin3 [CUL3]). These four proteins are involved in the network of NCC activity-regulated signaling pathways. WNK1 and WNK4 regulate NCC activity through SPAK/OSR1 phosphorylation,[8] and KLHL3 and CUL3 modulate the degradation of WNK kinase through a ubiquitylation mechanism.[9],[10]

There are many different WNK1 isoforms expressed in mammals. Full-length WNK1 (also called long-WNK1, L-WNK1) contains the entire kinase domain, widely expressed in a variety of human tissues, while a shorter, kidney-specific WNK1 (KS-WNK1) is only expressed in the distal nephron and is devoid of kinase activity. In the initial study of Xenopus laevis oocytes, L-WNK1 was reported to antagonize the inhibitory effect of WNK4 on NCC instead of a direct NCC activation.[11] However, L-WNK1 phosphorylates SPAK, indicating that L-WNK1 can phosphorylate NCC through a SPAK-dependent mechanism.[6],[12] Recent studies have shown that WNK1 has several alternatively splicing isoforms of exons 9, 11, 12, and 26. The predominant isoform in the kidney is WNK1-Δ11 (only lacking exon 11), which was proved to be a potent activator of NCC in Xenopus oocytes.[13] Moreover, WNK1-FHHt mice (deletions in intron 1 of the WNK1 gene) fully showed FHHt phenotype with increased L-WNK1 expression and no change in KS-WNK1 expression. The mice also appeared increased phosphorylation levels of SPAK and NCC on DCT.[14] All above indicate that L-WNK1 activates NCC.

Like L-WNK1, WNK3 also activates NCC in vitro through a SPAK-dependent pathway.[15],[16] In contrast, the phosphorylation and expression levels of OSR1, SPAK, NKCC2, and NCC in the kidneys of WNK3 knockout mice were not reduced in either normal or low-salt diets, suggesting that WNK3's effect on NCC is minimal in vivo.[17]

Whether the effect of WNK4 on NCC is positive or negative had been debated for a long time. Studies employing heterologous expression of WNK4 in Xenopus oocytes [18],[19] and mammalian cell systems [13],[20] typically reported that WNK4 inhibited NCC. The experiment of mDCT15 cell line showed that reducing endogenous WNK4 using a small hairpin RNA was followed by an increase in NCC activity and membrane expression.[21] On the contrary, almost all in vivo data support that WNK4 activates NCC. The phosphorylation levels of SPAK and NCC were significantly reduced in WNK4 knockout (WNK4- KO) mice, showing a Gitelman-like phenotype including hypokalemia and metabolic alkalosis.[22] Although there was a marked increase in WNK1 expression, it could not compensate for WNK4 deficiency in the DCT, indicating that WNK4 is the major positive regulator of NCC in the kidney.[23] It was further supported by unique chloride-sensing properties of WNK4 (see below for details).[24] Animal models of FHHt disease mutant of WNK4 D561A knockin,[25],[26] transgenic mice carrying multiple copies of wild-type WNK4 gene,[9] and mice carrying KLHL3 mutations [27] were demonstrated to exhibit FHHt phenotype, showing without exception the increased abundance of WNK4 and phosphorylation of SPAK/OSR1 and NCC. Taken together, all these mouse models support that WNK4 has a positive effect on NCC.


  Chloride-Sensing Properties of WNK Kinases Top


WNK kinases are reported to be chloride-sensitive. Recent studies have shown that the intracellular chloride concentration [Cl ]i inhibits autophosphorylation and activity of WNK1 and WNK4, thereby preventing NCC phosphorylation. Piala et al.[28] reported that two key leucine residues, Leu369 and Leu371 in the L-WNK1 kinase domain, can bind to Cl , thereby abolishing the autophosphorylation and activation of the kinase. Similarly, the effect of WNK4 on NCC is also regulated by [Cl ]i. Mutating Leu322 in WNK4 impeded the binding between WNK4 and Cl , resulting in the constitutive phosphorylation and activation of WNK4.[29] WNK4 is inhibited at high [Cl ]i.[13] Conversely, WNK4 can be phosphorylated at low [Cl ]i. Furthermore, WNKs have different chloride affinity. Compared with WNK1 and WNK3, WNK4 is the most sensitive to [Cl ]i. The affinity profile is probably WNK4 >WNK1 >WNK3.[24]


  Sodium-Chloride Cotransporter Regulation by Extracellular K + Top


Nowadays, individuals consuming a Western diet typically ingest approximately 50–100 mEq (2–4 g) potassium daily,[30],[31] which is much less than our ancestors thousands of years ago. In the body, most of K + is located inside the cell while extracellular fluid contains only 50–80 mEq K +. Thus, even a single meal might contain more K + than that is present in the extracellular fluid, presenting a substantial physiologic challenge. A HK meal might raise plasma K +, and plasma K + is buffered by both renal and extrarenal mechanisms. Approximately 90% of the daily intake of K + is excreted from the kidneys by urine and <10% is excreted by the gastrointestinal tract. Plasma K + also can be reduced by transferring K + into the cells. Thus, large and potential harmful swings in plasma K + typically do not occur during the day, and kidneys play a dominant role in K + balance. Several studies demonstrated that NCC phosphorylation is modulated by dietary potassium intake. HK diet suppresses [32],[33] and LK intake increases [34],[35] NCC activity.

Recently, an elegant experiment performed by Terker et al.[24] convincingly proved that the activity of the WNK-SPAK signaling pathway in the DCT is regulated by extracellular K + such that hyperkalemia inhibits, whereas hypokalemia stimulates NCC phosphorylation. A possible hypothesis for the explanation of such effects comes from recent observations in a mouse model of EAST/SeSAME syndrome. EAST/SeSAME syndrome is an autosomal recessive disease, caused by loss-of-function mutations in the KCNJ10 gene. The KCNJ10 gene encodes an inwardly rectifying potassium channel 4.1 (Kir4.1) that is expressed in certain neurons and in the basolateral plasma membrane of the DCT. Kir4.1 activity is essential for maintaining cell membrane potential. Intracellular K + leaves the cell through activated Kir4.1, which promotes DCT cell hyperpolarization with a consequent chloride efflux, thus decreasing [Cl ]i activating NCC through a WNK4-SPAK-dependent mechanism.[36]KCNJ10 knockout mice showed that impaired Kir4.1 activity resulted in depolarizing basolateral membrane of DCT cells and reducing the electrochemical driving force of ClC-K Cl channels, which raised [Cl ]i and then inhibited WNK-SPAK-NCC cascade.[37],[38] Therefore, the activity of Kir4.1 plays a key role in the regulation of NCC activity, and the increase in [Cl ]i induced by membrane depolarization is responsible for the inhibition of NCC activity in DCT cells expressing loss-of-function mutants of KCNJ10.[36] Terker et al.[36] reported extracellular K + modulates Kir4.1 directly, by which hyperkalemia depolarizes membrane potential, finally leading to NCC inactivation, and vice versa. Furthermore, the modest change of plasma K + within the physiological range, which is often seen in daily life, is enough to induce different levels of NCC phosphorylation.[24]

Apart from regulating the WNK-SPAK-NCC cascade by a Cl dependent pathway, evidence emerged from several different groups suggesting extracellular K + can also modulate NCC phosphorylation through additional signaling pathway which is likely to be Cl independent. For example, SPAK/OSR1 single- and double-knockout mice were still able to modulate NCC phosphorylation to some extent in response to LK intake,[36],[39] indicating another regulation pathway of NCC in which WNK-SPAK/OSR1 are not involved. NCC dephosphorylation triggered by HK is neither blocked by removing extracellular Cl nor by the Cl channel blocker 4,4'-diisothiocyano-2,2'-stilbenedisulphonic acid.[40] Ishizawa et al.[41] demonstrated that the KLHL3/CUL3-based ubiquitin ligase is involved in the LK-mediated activation of NCC. Shoda et al.[42] proposed that HK diet can activate calcineurin, which dephosphorylates NCC quickly, promoting urinary potassium excretion.


  The Effect of Aldosterone Top


Aldosterone is regarded as a principal hormone handling renal K + excretion while it also regulates Na + balance and blood pressure. When HK diet increases plasma K +, aldosterone is secreted by adrenal zona glomerulosa to promote renal excretion of potassium. Aldosterone binds to mineralocorticoid receptor (MR) and then activates ENaC. The inwardly rectifying K + channel ROMK excretes K + with the help of the negative potential of lumen generated by ENaC. Several groups reported that mice treated with direct infusion of aldosterone [43] or dietary salt restriction [25],[44] displayed an increase of plasma aldosterone and NCC activation, so the authors concluded that aldosterone can activate NCC.[45] However, a recent study showed deficient NCC activity in renal MR knockout mice and NCC could be activated by restricting dietary K +, suggesting that aldosterone's effect on NCC is secondary to the changes in plasma K +, rather than direct activation.[46] Moreover, NCC phosphorylation was no more incurred in wide-type mice fed with HK diet to correct the hypokalemia caused by aldosterone injection.[46] Todkar et al.[47] found NCC phosphorylation could still be inhibited in aldosterone synthase gene knockout (AS −/−) on HK diet although the abundance of ENaC and ROMK was higher in AS −/− than AS +/+. In addition, the nephron-specific α-subunit of ENaC knockout mice fed a regular-salt diet exhibited downregulated expression and phosphorylation of NCC, despite high plasma aldosterone levels.[48],[49] It is worth noting that urinary K + excretion induced by HK diet is often present before serum aldosterone is elevated, suggesting alternative aldosterone-independent pathway such as Maxi-K (BK) for K + excretion.[33]


  Summary Top


NCC can be directly regulated by extracellular K +, and it serves as an extracellular K + sensor to switch on or off downstream K + excretion. Extracellular K + changes the cell membrane potential in distal tubule through Kir4.1, affecting [Cl ]i. When [K +]ex is high, [Cl ]i is increased and vice versa. WNKs are chloride-sensing kinases, when binding to Cl , the dephosphorylation of WNK4 inhibits downstream phosphorylation of SPAK/OSR1 and NCC. In addition, extracellular K + can also modulate NCC phosphorylation through a WNK-SPAK/OSR1 and chloride-independent manner which remains to be clarified.


  Prospective Top


Compared to diets consumed by our evolutionary ancestors, most people in the world today consume a diet relatively high in salt and low in K +. The distal tubule of the mammalian kidney is designed to facilitate K + excretion which is accommodated to HK diet of ancient times. Unrestricted activation of NCC caused by typical modern LK diet is likely account for the rapid rise in hypertension prevalence, which is a major public health issue. HK diet intake is proved to result in lowered blood pressure and decreased mortality in the population. Figuring out the mechanism of NCC regulation by extracellular K + holds considerable promise for the development of novel antihypertensive drugs and diuretics.

Financial support and sponsorship

This work was supported by the National Natural Science Foundation of China 81570634 and 81770706.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rubera I, Loffing J, Palmer LG, Frindt G, Fowler-Jaeger N, Sauter D, et al. Collecting duct-specific gene inactivation of alphaENAC in the mouse kidney does not impair sodium and potassium balance. J Clin Invest 2003;112:554-65.  Back to cited text no. 1
    
2.
Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, et al. Gitelman's variant of bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 1996;12:24-30.  Back to cited text no. 2
    
3.
Bandulik S, Schmidt K, Bockenhauer D, Zdebik AA, Humberg E, Kleta R, et al. The salt-wasting phenotype of EAST syndrome, a disease with multifaceted symptoms linked to the KCNJ10 K+ channel. Pflugers Arch 2011;461:423-35.  Back to cited text no. 3
    
4.
Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, et al. Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med 2009;360:1960-70.  Back to cited text no. 4
    
5.
Pacheco-Alvarez D, Cristóbal PS, Meade P, Moreno E, Vazquez N, Muñoz E, et al. The Na+:Cl- cotransporter is activated and phosphorylated at the amino-terminal domain upon intracellular chloride depletion. J Biol Chem 2006;281:28755-63.  Back to cited text no. 5
    
6.
Richardson C, Rafiqi FH, Karlsson HK, Moleleki N, Vandewalle A, Campbell DG, et al. Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1. J Cell Sci 2008;121:675-84.  Back to cited text no. 6
    
7.
Rafiqi FH, Zuber AM, Glover M, Richardson C, Fleming S, JovanovičS, et al. Role of the WNK-activated SPAK kinase in regulating blood pressure. EMBO Mol Med 2010;2:63-75.  Back to cited text no. 7
    
8.
Shekarabi M, Zhang J, Khanna AR, Ellison DH, Delpire E, Kahle KT, et al. WNK kinase signaling in ion homeostasis and human disease. Cell Metab 2017;25:285-99.  Back to cited text no. 8
    
9.
Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, et al. Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension. Cell Rep 2013;3:858-68.  Back to cited text no. 9
    
10.
Shibata S, Zhang J, Puthumana J, Stone KL, Lifton RP. Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4. Proc Natl Acad Sci U S A 2013;110:7838-43.  Back to cited text no. 10
    
11.
Yang CL, Zhu X, Wang Z, Subramanya AR, Ellison DH. Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport. J Clin Invest 2005;115:1379-87.  Back to cited text no. 11
    
12.
Moriguchi T, Urushiyama S, Hisamoto N, Iemura S, Uchida S, Natsume T, et al. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. J Biol Chem 2005;280:42685-93.  Back to cited text no. 12
    
13.
Chávez-Canales M, Zhang C, Soukaseum C, Moreno E, Pacheco-Alvarez D, Vidal-Petiot E, et al. WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4. Hypertension 2014;64:1047-53.  Back to cited text no. 13
    
14.
Vidal-Petiot E, Elvira-Matelot E, Mutig K, Soukaseum C, Baudrie V, Wu S, et al. WNK1-related familial hyperkalemic hypertension results from an increased expression of L-WNK1 specifically in the distal nephron. Proc Natl Acad Sci U S A 2013;110:14366-71.  Back to cited text no. 14
    
15.
Cruz-Rangel S, Melo Z, Vázquez N, Meade P, Bobadilla NA, Pasantes-Morales H, et al. Similar effects of all WNK3 variants on SLC12 cotransporters. Am J Physiol Cell Physiol 2011;301:C601-8.  Back to cited text no. 15
    
16.
Pacheco-Alvarez D, Vázquez N, Castañeda-Bueno M, de-Los-Heros P, Cortes-González C, Moreno E, et al. WNK3-SPAK interaction is required for the modulation of NCC and other members of the SLC12 family. Cell Physiol Biochem 2012;29:291-302.  Back to cited text no. 16
    
17.
Oi K, Sohara E, Rai T, Misawa M, Chiga M, Alessi DR, et al. A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC co-transporters in vivo. Biol Open 2012;1:120-7.  Back to cited text no. 17
    
18.
Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: The Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci U S A 2003;100:680-4.  Back to cited text no. 18
    
19.
Yang CL, Angell J, Mitchell R, Ellison DH. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J Clin Invest 2003;111:1039-45.  Back to cited text no. 19
    
20.
Cai H, Cebotaru V, Wang YH, Zhang XM, Cebotaru L, Guggino SE, et al. WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells. Kidney Int 2006;69:2162-70.  Back to cited text no. 20
    
21.
Ko B, Mistry AC, Hanson L, Mallick R, Cooke LL, Hack BK, et al. A new model of the distal convoluted tubule. Am J Physiol Renal Physiol 2012;303:F700-10.  Back to cited text no. 21
    
22.
Castañeda-Bueno M, Cervantes-Pérez LG, Vázquez N, Uribe N, Kantesaria S, Morla L, et al. Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process. Proc Natl Acad Sci U S A 2012;109:7929-34.  Back to cited text no. 22
    
23.
Takahashi D, Mori T, Nomura N, Khan MZ, Araki Y, Zeniya M, et al. WNK4 is the major WNK positively regulating NCC in the mouse kidney. Biosci Rep 2014;34:e107.  Back to cited text no. 23
    
24.
Terker AS, Zhang C, Erspamer KJ, Gamba G, Yang CL, Ellison DH, et al. Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis. Kidney Int 2016;89:127-34.  Back to cited text no. 24
    
25.
Chiga M, Rai T, Yang SS, Ohta A, Takizawa T, Sasaki S, et al. Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. Kidney Int 2008;74:1403-9.  Back to cited text no. 25
    
26.
Yang SS, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, et al. Molecular pathogenesis of pseudohypoaldosteronism type II: Generation and analysis of a WNK4(D561A/+) Knockin mouse model. Cell Metab 2007;5:331-44.  Back to cited text no. 26
    
27.
Wu G, Peng JB. Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation. FEBS Lett 2013;587:1717-22.  Back to cited text no. 27
    
28.
Piala AT, Moon TM, Akella R, He H, Cobb MH, Goldsmith EJ, et al. Chloride sensing by WNK1 involves inhibition of autophosphorylation. Sci Signal 2014;7:ra41.  Back to cited text no. 28
    
29.
Bazúa-Valenti S, Chávez-Canales M, Rojas-Vega L, González-Rodríguez X, Vázquez N, Rodríguez-Gama A, et al. The effect of WNK4 on the Na+-Cl- cotransporter is modulated by intracellular chloride. J Am Soc Nephrol 2015;26:1781-6.  Back to cited text no. 29
    
30.
Cogswell ME, Zhang Z, Carriquiry AL, Gunn JP, Kuklina EV, Saydah SH, et al. Sodium and potassium intakes among US adults: NHANES 2003-2008. Am J Clin Nutr 2012;96:647-57.  Back to cited text no. 30
    
31.
Mente A, O'Donnell MJ, Rangarajan S, McQueen MJ, Poirier P, Wielgosz A, et al. Association of urinary sodium and potassium excretion with blood pressure. N Engl J Med 2014;371:601-11.  Back to cited text no. 31
    
32.
Rengarajan S, Lee DH, Oh YT, Delpire E, Youn JH, McDonough AA, et al. Increasing plasma [K+] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis. Am J Physiol Renal Physiol 2014;306:F1059-68.  Back to cited text no. 32
    
33.
Sorensen MV, Grossmann S, Roesinger M, Gresko N, Todkar AP, Barmettler G, et al. Rapid dephosphorylation of the renal sodium chloride cotransporter in response to oral potassium intake in mice. Kidney Int 2013;83:811-24.  Back to cited text no. 33
    
34.
Castañeda-Bueno M, Cervantes-Perez LG, Rojas-Vega L, Arroyo-Garza I, Vázquez N, Moreno E, et al. Modulation of NCC activity by low and high K(+) intake: Insights into the signaling pathways involved. Am J Physiol Renal Physiol 2014;306:F1507-19.  Back to cited text no. 34
    
35.
Vitzthum H, Seniuk A, Schulte LH, Müller ML, Hetz H, Ehmke H, et al. Functional coupling of renal K+ and Na+ handling causes high blood pressure in Na+ replete mice. J Physiol 2014;592:1139-57.  Back to cited text no. 35
    
36.
Terker AS, Zhang C, McCormick JA, Lazelle RA, Zhang C, Meermeier NP, et al. Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride. Cell Metab 2015;21:39-50.  Back to cited text no. 36
    
37.
Cuevas CA, Su XT, Wang MX, Terker AS, Lin DH, McCormick JA, et al. Potassium sensing by renal distal tubules requires Kir4.1. J Am Soc Nephrol 2017;28:1814-1825.  Back to cited text no. 37
    
38.
Zhang C, Wang L, Zhang J, Su XT, Lin DH, Scholl UI, et al. KCNJ10 determines the expression of the apical Na-Cl cotransporter (NCC) in the early distal convoluted tubule (DCT1). Proc Natl Acad Sci U S A 2014;111:11864-9.  Back to cited text no. 38
    
39.
Wade JB, Liu J, Coleman R, Grimm PR, Delpire E, Welling PA, et al. SPAK-mediated NCC regulation in response to low-K+diet. Am J Physiol Renal Physiol 2015;308:F923-31.  Back to cited text no. 39
    
40.
Penton D, Czogalla J, Wengi A, Himmerkus N, Loffing-Cueni D, Carrel M, et al. Extracellular K + rapidly controls NaCl cotransporter phosphorylation in the native distal convoluted tubule by Cl - -dependent and independent mechanisms. J Physiol 2016;594:6319-331.  Back to cited text no. 40
    
41.
Ishizawa K, Xu N, Loffing J, Lifton RP, Fujita T, Uchida S, et al. Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3. Biochem Biophys Res Commun 2016;480:745-51.  Back to cited text no. 41
    
42.
Shoda W, Nomura N, Ando F, Mori Y, Mori T, Sohara E, et al. Calcineurin inhibitors block sodium-chloride cotransporter dephosphorylation in response to high potassium intake. Kidney Int 2017;91:402-11.  Back to cited text no. 42
    
43.
Velázquez H, Bartiss A, Bernstein P, Ellison DH. Adrenal steroids stimulate thiazide-sensitive NaCl transport by rat renal distal tubules. Am J Physiol 1996;270:F211-9.  Back to cited text no. 43
    
44.
van der Lubbe N, Moes AD, Rosenbaek LL, Schoep S, Meima ME, Danser AH, et al. K+-induced natriuresis is preserved during Na+depletion and accompanied by inhibition of the Na+-Cl- cotransporter. Am J Physiol Renal Physiol 2013;305:F1177-88.  Back to cited text no. 44
    
45.
Kim GH, Masilamani S, Turner R, Mitchell C, Wade JB, Knepper MA, et al. The thiazide-sensitive Na-Cl cotransporter is an aldosterone-induced protein. Proc Natl Acad Sci U S A 1998;95:14552-7.  Back to cited text no. 45
    
46.
Terker AS, Yarbrough B, Ferdaus MZ, Lazelle RA, Erspamer KJ, Meermeier NP, et al. Direct and indirect mineralocorticoid effects determine distal salt transport. J Am Soc Nephrol 2016;27:2436-45.  Back to cited text no. 46
    
47.
Todkar A, Picard N, Loffing-Cueni D, Sorensen MV, Mihailova M, Nesterov V, et al. Mechanisms of renal control of potassium homeostasis in complete aldosterone deficiency. J Am Soc Nephrol 2015;26:425-38.  Back to cited text no. 47
    
48.
Mordasini D, Loffing-Cueni D, Loffing J, Beatrice R, Maillard MP, Hummler E, et al. ENaC activity in collecting ducts modulates NCC in cirrhotic mice. Pflugers Arch 2015;467:2529-39.  Back to cited text no. 48
    
49.
Perrier R, Boscardin E, Malsure S, Sergi C, Maillard MP, Loffing J, et al. Severe salt-losing syndrome and hyperkalemia induced by adult nephron-specific knockout of the epithelial sodium channel α-subunit. J Am Soc Nephrol 2016;27:2309-18.  Back to cited text no. 49
    




 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
WNK-Ste20-Relate...
Sodium-Chloride ...
The Effect of Al...
Summary
Prospective
Chloride-Sensing...
References

 Article Access Statistics
    Viewed360    
    Printed7    
    Emailed0    
    PDF Downloaded44    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]