Verrey, Francois

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Translational NephrologyWNK4, as thiazides, shuts off NaCl reabsorption to stimulateNa/K exchangeFrancois VerreyInstitute of Physiology and Centre for Integrative Human Physiology (ZIHP), University of Zu¨rich, Winterthurerstrasse 190,CH-8057 Zu¨rich, SwitzerlandKeywords: aldosterone; arterial blood pressure;distal convoluted tubule; Familial hyperkalemichypertension; Gordon’s syndrome; Kþ secretion;NaCl reabsorption; thiazidesIn a manuscript recently published in Nature Genetics,Lalioti et al. [1] show that Wnk4 switches distalnephron function from NaCl reabsorption to Naþ/Kþexchange, mainly by dismantling the Na–Cl cotrans-porter expressing distal convoluted tubule segmentDCT1. Interestingly, the structural integrity of thissegment had already been shown long ago to dependon Na–Cl cotransporter function, as thiazidesprovoke similar DCT1 regression as Wnk4overexpression [2].The observation underlying the study by Laliotiet al. is that the rare autosomal dominant form ofarterial hypertension Familial hyperkalemic hyperten-sion (FHHt), also called Pseudohypoaldosteronismtype II (PHAII) or Gordon’s Syndrome, is caused bymutations in the gene encoding the protein kinaseWNK1 or WNK4 [3]. The salient feature of FHHt isthe unusual combination of Naþ and Kþ retention.Additional symptoms are hyperchloraemia and meta-bolic acidosis. The central physiological question thatis tackled by this monogenetic disease is how thedifferential response of the kidney to high potassiumintake and/or to low extracellular volume (low NaCl)is coordinated and organized, in particular in view ofthe fact that both hypokalaemia and hypovolaemia arestrong stimulators of aldosterone secretion.First let us briefly mention how mutations in twodifferent genes encoding related protein kinases lead tosimilar clinical features. In FHHt caused by mutationsin the gene encoding WNK1, an intronic deletion leadsto its increased expression, whereas in FHHt caused byWNK4, the mutations affect amino acids of a shortspecific region of this kinase [3]. As shown in Figure 1,WNK4 and WNK1 interact within a regulatorycascade that controls the thiazide-sensitive Na–Clcotransporter NCC [4,5]. This explains how anincrease in WNK1 expression can have the sameeffect as a mutation that prevents WNK4 frominhibiting NCC.Transgenic mice expressing wild-type or FHHtmutant Wnk4To address the question of the effect of Wnk4 and ofits FHHt mutation in vivo, Lalioti et al. [1] generatedtransgenic mice harboring two additional genomicWnk4 copies with and without an FHHt causativemutation. Importantly, the axial localization of these(over)expressed Wnk4 proteins along the nephron andtheir subcellular localization were found unchanged.The telemetrically measured mean systolic arterialblood pressure of Tg(Wnk4WT) mice was significantlylower (109mmHg) than that of control littermates(117mmHg), whereas that of Tg(Wnk4FHHt) mice wassignificantly higher (124mmHg). In Tg(Wnk4WT)mice, serum Kþ and HCO3 were unchanged, Cland Mg2þ slightly decreased and calciuria decreasedcompared to control littermates. In contrast, inTg(Wnk4FHHt) mice, serum Kþ, Cl and Mg2þ weresignificantly increased, HCO3 decreased and calciuriaincreased, recapitulating the situation known forFamilial hyperkalemic hypertension. Upon a high Kþdiet, mice harboring the FHHt transgene showed aclear defect in urinary Kþ secretion which led to theirdeath within several days, whereas the mice harboringthe WT transgene maintained a lower Kþ level thancontrol littermates.*Comment on Lalioti, MD, Zhang J, Volkman HM et al. Wnk4controlsblood pressure and potassium homeostasis via regulation ofmass and activity of the distal convoluted tubule. Nat Genet 2006;38: 1124–1132.Correspondence and offprint requests to: Franc¸ois Verrey, Instituteof Physiology, University of Zu¨rich, Winterthurerstrasse 190,CH-8057 Zu¨rich, Switzerland. Email: verrey@access.unizh.chNephrol Dial Transplant (2007) 22: 1305–1308doi:10.1093/ndt/gfm010Advance Access publication 17 February 2007 The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please email: journals.permissions@oxfordjournals.orgInhibition of NCC by Wnk4 triggers dismantling ofthe DCT1 nephron segmentMorphological analysis of the kidneys byimmunostaining showed that the main differencebetween the Wnk4 genotypes was the size of the firstpart of the distal convoluted tubule also calledDCT1 (Figure 2) [1]. This is the segment that expressesas sole apical Naþ transport protein the thiazide-sensitive Na–Cl cotransporter NCC. Whereas inTg(Wnk4FHHt) mice this nephron segment was hyper-trophied compared to littermates, its size (length andsize of cells) was strongly reduced in Tg(Wnk4WT) miceas previously observed after thiazide treatment of ratsand in NCC/ mice [2,6]. Correspondingly, theamount of NCC mRNA was also strongly changed,whereas the mRNAs of ROMK1 and ENaC, the mainluminal channels of the following tubular segments,were not much affected. To confirm the central roleplayed by the Na–Cl cotransporter for this regulation,NCC/ alleles were bred into the Tg(Wnk4FHHt)background. Importantly, the knock out of NCCreverted the phenotype of the Wnk4 FHHt transgenicFig. 2. Wnk4 switches the distal nephron from Cl reabsorption to Kþ secretion. The impact of transgenic Wnk4 WT and mutant alleles isshown in a simplified two-compartment model [15]. As shown in the left panels, wild-type Wnk4 overexpression inhibits NCC and this leadsto regression of the distal convoluted tubule segment DCT1, similar to that observed with pharmacological NCC inhibition by thiazides orwith genetic NCC disruption (Gitelman’s syndrome). The consequent lack of NaCl reabsorption in DCT1 increases the Naþ load to thefollowing DCT2 and CNT segments that express ENaC such that increased electrogenic Naþ reabsorption drives Kþ secretion throughROMK and maxi K channels. A similar situation is observed under high Kþ diet. A mirror image situation corresponding to FamilialHyperkalemic Hypertension is observed when the dominant Wnk4 FHHt allele is expressed (right panels). This leads to a lack of NCCinhibition, such that very little Naþ reaches the following ENaC expressing segments, leading to a defect in Kþ secretion. A similar activationof NCC is also observed when the renin-angiotensin-aldosterone system is induced by low NaCl diet. Unlike in FHHt, there is highaldosterone in this condition that stimulates ENaC expressing segments.Na+Cl−Wnk4Wnk1-LWnk1-SFig. 1. Inhibition/down-regulation of Na–Cl cotransporter NCC byWnk4. This simplified scheme shows that the Wnk4 meditatedinhibition/downregulation of NCC can be relieved by full lengthWnk1 (Wnk1-L¼L-Wnk1). This effect of Wnk1-L indirectlyactivates NCC and can in turn be prevented by the kidney-specificshort Wnk1 transcript Wnk1-S (KS-WNK1) that thereby indirectlyinhibits NCC function/expression [5,19,20].1306 F. Verreymice at the morphological and at the functional levels,to a phenotype very similar to that of the Wnk4 WTtransgenic mice. However, the intriguing question ofhow Na–Cl cotransport activity via NCC controls theepithelial cell number and size of the DCT1 segmentremains open.Do the other Wnk4 functions described in vitro playa physiological role?The reversal of the FHHt phenotype by knocking outNCC raises the question as to whether any action ofWnk4, other than NCC inhibition, is physiologicallyrelevant. Indeed, many coexpression studies of wild-type WNK4 with proteins potentially participating inthe FHHt phenotype suggested additional effects ofthis kinase, in particular the inhibition of ROMK1,TRPV4, NKCC1 and Kþ–Cl-cotransporters and theup-regulation of TRPV5 and of the paracellular Clpermeability [7–13]. In this respect, one can concludefrom the experiments presented in the paper of Laliotiet al. that in the physiological conditions tested,potential additional effects of Wnk4 are not requiredto explain the phenotypes [14]. This means probablythat the functional effects mediated via NCC areclearly dominant in the tested overexpression condi-tions (Figure 2). However, this does not mean thatsome of the other effects described in vitro do notparticipate in the graded physiological effects that lieon the continuum between the tested extremes. In thiscontext, it is important to note that the experimentsdescribed by Lalioti et al. clearly demonstrate thatWnk4 must have a tonic activity in control conditions,since the regulation of the NCC compartment byWNK4 can act both ways, towards building up ordismantling DCT1. The very powerful but quiteenergy-consuming Kþ secretion system that is drivenby Naþ reabsorption via ENaC can indeed functiononly when sufficient luminal Naþ is available down-stream of the NCC compartment, that is when NaClreabsorption via NCC is not maximal [15].Interestingly, the ENaC and K channel-mediatedNaþ/Kþ exchange system situated downstream of theNCC compartment appears to be activated even moreefficiently by the need for increased Kþ secretion thanby low Naþ conditions [16,17].ConclusionsTaken together, the study by Lalioti et al. stresses thecentral role of thiazide-sensitive Na–Cl cotransporter(NCC) regulation for extracellular volume control.Wnk4 is elegantly shown in vivo to be a strongnegative regulator of NCC expression, whereas itsmutant form which causes dominant FHHt has theopposite effect. By tuning NaCl reabsorption at thelevel of the DCT1, the regulatory network of WNK’sswitches the action of aldosterone from supportingNaCl reabsorption, in the case of hypovolaemia,to that of stimulating the secretion of Kþ in the caseof hyperkalaemia. One clear difference betweenthe stimulation of aldosterone in the context ofhypovolaemia compared to its stimulation by hyper-kalaemia is the activation via the renin–angiotensinsystem. As suggested by the authors of the Wnk4transgene study, it could be that angiotensin II itselfplays a regulatory role here, at the level of the kidneytubule [1].However, how potassium intake controls Wnk4activity and thus the activity of Na–Cl cotransportand the integrity of the distal convoluted tubule remainopen questions. Finally, it appears likely that geneticvariants of WNK’s (expression) and thus of distalconvoluted tubule integrity and function impact onindividual arterial blood pressure regulation [1,18].Conflict of interest statement. None declared.References1. Lalioti MD, Zhang J, Volkman HM et al. Wnk4 controls bloodpressure and potassium homeostasis via regulation of mass andactivity of the distal convoluted tubule. Nat Genet 2006; 38:1124–11322. Loffing J, Loffing-Cueni D, Hegyi I et al. Thiazide treatment ofrats provokes apoptosis in distal tubule cells. Kidney Int 1996;50: 1180–11903. Wilson FH, Disse-Nicodeme S, Choate KA et al. Humanhypertension caused by mutations in WNK kinases. Science2001; 293: 1107–11124. Faure S, Delaloy C, Leprivey V et al. WNK kinases, distaltubular ion handling and hypertension. Nephrol Dial Transplant2003; 18: 2463–24675. Naray-Fejes-Toth A, Snyder PM, Fejes-Toth G. The kidney-specific WNK1 isoform is induced by aldosterone and stimulatesepithelial sodium channel-mediated Naþ transport. Proc NatlAcad Sci USA 2004; 101: 17434–174396. Loffing J, Vallon V, Loffing-Cueni D et al. Altered renal distaltubule structure and renal Na(þ) and Ca(2þ) handling in amouse model for Gitelman’s syndrome. J Am Soc Nephrol 2004;15: 2276–22887. Kahle KT, Wilson FH, Leng Q et al. WNK4 regulates thebalance between renal NaCl reabsorption and Kþ secretion. NatGenet 2003; 35: 372–3768. Fu Y, Subramanya A, Rozansky D et al. WNK kinasesinfluence TRPV4 channel function and localization. Am JPhysiol Renal Physiol 2006; 290: 1305–13149. Kahle KT, Gimenez I, Hassan H et al. WNK4 regulates apicaland basolateral Cl flux in extrarenal epithelia. Proc Natl AcadSci USA 2004; 101: 2064–206910. Garzon-Muvdi T, Pacheco-Alvarez D, Gagnon KB et al.WNK4Kinase is a Negative Regulator of Kþ-Cl Cotransporters. Am JPhysiol Renal Physiol 2006; in press11. Jiang Y, Ferguson WB, Peng JB. WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria offamilial hyperkalemic hypertension caused by gene mutationof WNK4. Am J Physiol Renal Physiol 2006; in press12. Kahle KT, Macgregor GG, Wilson FH et al. Paracellular Clpermeability is regulated by WNK4 kinase: insight into normalphysiology and hypertension. Proc Natl Acad Sci USA 2004;101: 14877–1488213. Yamauchi K, Rai T, Kobayashi K et al. Disease-causing mutantWNK4 increases paracellular chloride permeability andWNK4 and NaCL reabsorption 1307phosphorylates claudins. Proc Natl Acad Sci USA 2004; 101:4690–469414. Hadchouel J, Jeunemaitre X. Life and death of the distalnephron: WNK4 and NCC as major players. Cell Metab 2006;4: 335–33715. O’Reilly M, Marshall E, Macgillivray T et al. Dietaryelectrolyte-driven responses in the renal WNK kinase pathwayin vivo. J Am Soc Nephrol 2006; 17: 2402–241316. Meneton P, Loffing J, Warnock DG. Sodium and potassiumhandling by the aldosterone-sensitive distal nephron: the pivotalrole of the distal and connecting tubule. Am J Physiol RenalPhysiol 2004; 287: F593–F60117. Loffing-Cueni D, Schlaepfer M, Bloch-Faure M et al. Apicaltranslocation of ROMK and ENaC in mouse distal nephron inresponse to high K diet (Abstract). Nephrol Dial Transplant2003; 18: 55218. Levy D, DeStefano AL, Larson MG et al. Evidence for a geneinfluencing blood pressure on chromosome 17. Genome scanlinkage results for longitudinal blood pressure phenotypes insubjects from the Framingham heart study. Hypertension 2000;36: 477–48319. Subramanya AR, Yang CL, Zhu X et al. Dominant-negativeregulation of WNK1 by its kidney-specific kinase-defectiveisoform. Am J Physiol Renal Physiol 2006; 290: F619–F62420. O’Reilly M, Marshall E, Speirs HJ et al.WNK1, a gene within anovel blood pressure control pathway, tissue-specifically gen-erates radically different isoforms with and without a kinasedomain. J Am Soc Nephrol 2003; 14: 2447–2456Received for publication: 2.1.07Accepted in revised form: 5.1.071308 F. Verrey

WNK4, as thiazides, shuts off NaCl reabsorption to stimulate Na/K exchange

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