WNK kinases regulate thiazide-sensitive Na-Cl cotransport

Yang, Chao; Angell, Jordan; Mitchell, Rose; Ellison, David H.

doi:10.1172/jci17443

Cited by 403 publications

(405 citation statements)

References 23 publications

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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%

“…The RGS2 gene maps to chromosome 1q31, the locus for one form of monogenic hypertension, pseudohypoaldosteronism II . Yang et al (2003) identified five missense variations in the RGS2 gene in a Japanese population. All of them, however, occurred as rare mutations (<1% allele frequency) only in their hypertensive cohort.…”

Section: Genetic Variants Of the Regulator Of G Protein Signalling (Rmentioning

confidence: 99%

“…In addition to these rare mutations, they identified two common RGS2 polymorphisms (T1026A located in intron 1, and 1891-1892del TC, located in intron 2) which were associated with hypertension. These associations, however, were only significant in women, the biological plausibility of which remains to be studied (Yang et al 2003). Riddle and colleagues (2006) followed a similar approach in white and black Americans, and identified 16 variants in the RGS2 gene.…”

Section: Genetic Variants Of the Regulator Of G Protein Signalling (Rmentioning

confidence: 99%

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

confidence: 99%

Section: Genetic Variants Of the Regulator Of G Protein Signalling (Rmentioning

confidence: 99%

Section: Genetic Variants Of the Regulator Of G Protein Signalling (Rmentioning

confidence: 99%

See 1 more Smart Citation

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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“…This phenotype is the mirror image of Gitelman syndrome, and it was shown to result from gain-of-function of NCC [43]. While the exact mode of action of the different WNK kinases is still under debate, there are three abundant WNK kinases along the DCT, namely WNK1, WNK3, and WNK4, that affect NCC function by modulating trafficking and/or transport activity via phosphorylation [44]. Regulation of NCC by the WNK-SPAK signaling is an area of intense research and several studies also provided evidence for hormone regulation of the WNK-SPAK-NCC pathway (Figure 2) reviewed in [45] and [29].…”

Section: Functional Role Of Nccsvmentioning

confidence: 99%

Role of the alternative splice variant of NCC in blood pressure control

2018

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The renal thiazide-sensitive sodium-chloride cotransporter (NCC), located in the distal convoluted tubule (DCT) of the kidney, plays an important role in blood pressure regulation by fine-tuning sodium excretion. The human SLC12A3 gene, encoding NCC, gives rise to three isoforms, of which only the third isoform (NCC3) has been extensively investigated so far. However, recent studies unraveled the importance of the isoforms 1 and 2, collectively referred to as NCC splice variant (NCCSV), in several (patho)physiological conditions. In the human kidney, NCCSV localizes to the apical membrane of the DCT and could constitute a functional route for renal sodium-chloride reabsorption. Analysis of urinary extracellular vesicles (uEVs), a non-invasive method for measuring renal responses, demonstrated that NCCSV abundance changes in response to acute water loading and correlates with patients’ thiazide responsiveness. Furthermore, a novel phosphorylation site at serine 811 (S811), exclusively present in NCCSV, was shown to play an instrumental role in NCCSV as well as NCC3 function. This review aims to summarize these new insights of NCCSV function in humans that broadens the understanding on NCC regulation in blood pressure control.

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“…Utilisant les oeufs de xénope, deux équipes ont montré que WNK4 inhibe l'activité de transport de NCC, réduisant ainsi la réabsorption de sodium [17,18] (Figure 2 transcrits (Figure 4) produits grâce à: (1) un épissage alternatif des exons 9, 11 et 12, séparément ou conjointement; (2) la présence de deux sites de polyadényla-tion; (3) l'existence de plusieurs promoteurs. Le transcrit contenant l'ensemble des séquences codantes est majoritaire dans le coeur et le muscle squelettique.…”

Section: Wnk Et Réabsorption Sodée Dans Le Dctunclassified