Molecular pathogenesis of inherited hypertension with hyperkalemia: The Na–Cl cotransporter is inhibited by wild-type but not mutant WNK4

Wilson, Frederick H.; Kahle, Kristopher T.; Sabath, Ernesto; Lalioti, Maria D.; Rapson, Alicia K.; Hoover, Robert S.; Hebert, Steven C.; Gamba, Gerardo; Lifton, Richard P.

doi:10.1073/pnas.242735399

Cited by 378 publications

(371 citation statements)

References 21 publications

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“…The thiazide-sensitive Na-Cl co-transporter (NCC) in the distal convoluted tubule accounts for ~15% of sodium chloride reabsorption in the kidney. It was reported that wild type WNK4 inhibits the activity of NCC and disease-causing WNK4 mutants fail to inhibit NCC (Wilson et al, 2003;Yang et al, 2003). In addition, WNK4 phosphorylates claudins 1-4, the tight-junction proteins involved in the regulation of paracellular ion permeability (Kahle et al, 2004;Yamauchi et al, 2004).…”

Section: Pathogenesis Of Hypertension In Pha IImentioning

confidence: 99%

“…Wild type WNK4 also decreases surface expression of ROMK1 and WNK4 mutants that cause disease exhibit a greater inhibition of ROMK (Kahle et al, 2003;He et al, 2007), suggesting that increased inhibition of ROMK1 by mutant WNK4 may also contribute to hyperkalemia in PHA II patients with WNK4 mutations. Recent studies using transgenic and knock-in mice models, however, reported no detectable difference in the expression of ROMK between wild type mice and mice carrying transgenic or knock-in WNK4 mutant (Lalioti et al, 2006;Yang et al, 2007).…”

Section: Pathogenesis Of Hyperkalemia In Pha IImentioning

confidence: 99%

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WNKs: protein kinases with a unique kinase domain

Huang

Kuy²,

Wang³

et al. 2007

Exp Mol Med

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WNKs (with-no-lysine [K]) are a family of serine-threonine protein kinases with an atypical placement of the catalytic lysine relative to all other protein kinases. The roles of WNK kinases in regulating ion transport were first revealed by the findings that mutations of two members cause a genetic hypertension and hyperkalemia syndrome. More recent studies suggest that WNKs are pleiotropic protein kinases with important roles in many cell processes in addition to ion transport. Here, we review roles of WNK kinases in the regulation of ion balance, cell signaling, survival, and proliferation, and embryonic organ development.

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Section: Pathogenesis Of Hypertension In Pha IImentioning

confidence: 99%

Section: Pathogenesis Of Hyperkalemia In Pha IImentioning

confidence: 99%

WNKs: protein kinases with a unique kinase domain

Huang

Kuy²,

Wang³

et al. 2007

Exp Mol Med

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“…In contrast, activation of WNK1 inhibits the WNK4-mediated suppression of NCC transporter translocalization ( Fig. 8; Yang et al 2003;Wilson et al 2003) and requires kinase activity of WNK1.…”

Section: Gordon's Syndrome (Pseudohypoaldosteronism Type Ii)mentioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na + have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the reninangiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

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“…The lack of effect of cGMP and wortmannin indicates that neither PKG nor PI3K play a role in hNCC-mediated Na ϩ uptake. Recently, the serinethreonine kinase WNK4 was shown to associate with NCC and to reduce NCC membrane expression and NCC-mediated Na ϩ uptake after coexpression in Xenopus laevis oocytes (41).…”

Section: Discussionmentioning

confidence: 99%

Functional Expression of the Human Thiazide-Sensitive NaCl Cotransporter in Madin-Darby Canine Kidney Cells

Jong¹,

Willems²,

Heuvel³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. The thiazide-sensitive Na ϩ -Cl Ϫ cotransporter (NCC), which is expressed on the apical membrane of epithelial cells lining the distal convoluted tubule, is responsible for the reabsorption of 5% to 10% of filtered Na ϩ and Cl Ϫ . To date, functional studies on the structural and regulatory requirements for localized trafficking and ion-transporting activity of NCC have been hampered by lack of a suitable cell system expressing this cotransporter. Reported here is the functional expression of human NCC (hNCC) in a polarized mammalian cell of renal origin-that is, the high-resistance Madin-Darby canine kidney (MDCK) cell. Western blot testing revealed that the cells predominantly expressed the complex glycosylated (approximately 140 kD) form of hNCC. hNCC was present primarily in the apical part of the cell. The functionality of hNCC was demonstrated by the gain of thiazide-sensitive Na ϩ uptake and transepithelial transport activity. Na ϩ uptake was significantly increased after short-term (15 min) treatment with forskolin, whereas cyclic guanosine monophosphate, wortmannin, phorbol 12-myriatate 13-acetate, and staurosporine were without effect. This indicates that hNCC activity is regulated through cyclic adenosine monophosphate, rather than via cyclic guanosine monophosphate, phosphoinositide 3-kinases or protein kinase C. Aldosterone did not alter Na ϩ uptake in the short term (15 min) but significantly increased the transport activity in the long term (16 h). The latter effect of aldosterone was due to an effect on the cytomegalovirus promoter/enhancer driving the expression of hNCC. hNCC-MDCK cells are a good model for the study of the regulation of apical trafficking and ion-transporting activity of hNCC.

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Molecular pathogenesis of inherited hypertension with hyperkalemia: The Na–Cl cotransporter is inhibited by wild-type but not mutant WNK4

Cited by 378 publications

References 21 publications

WNKs: protein kinases with a unique kinase domain

WNKs: protein kinases with a unique kinase domain

Genetics of arterial hypertension and hypotension

Functional Expression of the Human Thiazide-Sensitive NaCl Cotransporter in Madin-Darby Canine Kidney Cells

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