Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule

Lalioti, Maria D.; Zhang, Junhui; Volkman, Heather M.; Kahle, Kristopher T.; Hoffmann, Kristin E; Toka, Hakan R.; Nelson‐Williams, Carol; Ellison, David H.; Flavell, Richard A.; Booth, Carmen J.; Lu, Yin; Geller, David S.; Lifton, Richard P.

doi:10.1038/ng1877

Cited by 337 publications

(379 citation statements)

References 30 publications

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“…Available hypotheses view WNK4 (and the isoforms of WNK1) as partners of a multiprotein complex that involves the homo-and heteromultimers of WNKs that exert scaffolding and kinase functions on downstream target proteins. Mice bearing a transgene with the human PHA2-mutant WNK4 develop hypertension, hyperkalemia and hypercalciuria, with dramatic structural changes of the distal convoluted tubule, including hyperplasia and massive expression of NCC (Lalioti et al 2006). This group suggested that PHA2B-causing mutations in negatively charged domains of WNK4 affect the ability to sense intracellular Ca 2+ levels, e.g.…”

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

confidence: 99%

“…Adrenal aldosterone release is stimulated either by volume contraction or hyperkalemia, situations which require different adaptations (sodium and water uptake vs sodium uptake coupled to potassium excretion) of the kidneys despite an identical signal. WNK4 activity could be the switch for this adaptation (Lalioti et al 2006).…”

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

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: 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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show abstract

“…Deletion of the Na + Cl − cotransporter (NCC) reversed most of the phenotypes seen in the transgenic mice harboring the PHAII-causing WNK4 mutants (5), which indicated that aberrant regulation of NCC by the mutant WNK4 is critically involved in the pathogenesis of PHAII. This finding led to the suggestion that increased Na + in systemic fluids by the altered NCC activity is associated with elevated blood pressure (7)(8)(9)(10).…”

mentioning

confidence: 99%

Serine-threonine kinase with-no-lysine 4 (WNK4) controls blood pressure via transient receptor potential canonical 3 (TRPC3) in the vasculature

Park¹,

Kim²,

Choi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the serine-threonine kinase with-no-lysine 4 (WNK4) cause pseudohypoaldosteronism type 2 (PHAII), a Mendelian form of human hypertension. WNK4 regulates diverse ion transporters in the kidney, and dysregulation of renal transporters is considered the main cause of the WNK4 mutation-associated hypertension. Another determinant of hypertension is vascular tone that is regulated by Ca 2+ -dependent blood vessel constriction. However, the role of WNK4 in vasoconstriction as part of its function to regulate blood pressure is not known. Here, we report that WNK4 is a unique modulator of blood pressure by restricting Ca 2+ influx via the transient receptor potential canonical 3 (TRPC3) channel in the vasculature. Loss of WNK4 markedly augmented TRPC3-mediated Ca 2+ influx in vascular smooth muscle cells (VSMCs) in response to α-adrenoreceptor stimulation, which is the pathological hallmark of hypertension in resistance arteries. Notably, WNK4 depletion induced hypertrophic cell growth in VSMCs and increased vasoconstriction in small mesenteric arteries via TRPC3-mediated Ca 2+ influx. In addition, WNK4 mutants harboring the Q562E PHAII-causing or the D318A kinase-inactive mutation failed to mediate TRPC3 inhibition. These results define a previously undescribed function of WNK4 and reveal a unique therapeutic target to control blood pressure in WNK4-related hypertension.H ypertension, or elevated arterial blood pressure, is one of the most common diseases in industrialized countries, increasing the risk of a wide spectrum of cardiovascular illnesses including stroke, congestive heart failure, and myocardial infarction (1). More than 90% of hypertensive patients are classified as essential hypertension because of the lack of knowledge regarding the gene identity involved in blood pressure regulation (2, 3). In the last few years, most attention has been focused on the with-no-lysine (WNK) kinases, including WNK4, that were found mutated in patients with pseudohypoaldosteronism type 2 (PHAII; Online Mendelian Inheritance in Man no. 145260), which is a rare autosomal dominant disorder featuring hypertension associated with hyperkalemia, hyperchloremia, and metabolic acidosis (4).Mice harboring the PHAII-causing WNK4 mutations Q562E (5) and D561A (6) reconstituted the phenotypes observed in PHAII patients. Deletion of the Na + Cl − cotransporter (NCC) reversed most of the phenotypes seen in the transgenic mice harboring the PHAII-causing WNK4 mutants (5), which indicated that aberrant regulation of NCC by the mutant WNK4 is critically involved in the pathogenesis of PHAII. This finding led to the suggestion that increased Na + in systemic fluids by the altered NCC activity is associated with elevated blood pressure (7-10). Another important aspect of hypertension is vascular tone. However, despite the diverse extrarenal tissue distribution of WNK4 (11), the expression and function of WNK4 in the resistance artery and the role in vasoconstriction as part of its function to regulate blood pressure has not been c...

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“…To date, a direct link between a particular gene impinging histone modifications to BP has not been clearly established. Second, numerous mouse models lacking ENaC and their direct or indirect regulators such as AS, 13 angiotensinogen (Agt), 14 angiotensin-converting enzyme (ACE), 15 MR, 16 Sgk1, 17 WNK1, 18 WNK4, 19 and Period 20 have been reported. However, the role of these models in showing the epigenetic control of BP is still unclear.…”

mentioning

confidence: 99%

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

Chen¹,

H²,

Pochynyuk

et al. 2011

Journal of the American Society of Nephrology

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The putative transcription factor AF17 upregulates the transcription of the epithelial sodium channel (ENaC) genes, but whether AF17 modulates sodium homeostasis and BP is unknown. Here, we generated Af17-deficient mice to determine whether deletion of Af17 leads to sodium wasting and low BP. Compared with wild-type mice, Af17-deficient mice had lower BP (11 mmHg), higher urine volume, and increased sodium excretion despite mildly increased plasma concentrations of aldosterone. Deletion of Af17 led to increased dimethylation of histone H3 K79 and reduced ENaC function. The attenuated function of ENaC resulted from decreased ENaC mRNA and protein expression, fewer active channels, lower open probability, and reduced effective activity. In contrast, inducing high levels of plasma aldosterone by a variety of methods completely compensated for Af17 deficiency with respect to sodium handling and BP. Taken together, these data identify Af17 as a potential locus for the maintenance of sodium and BP homeostasis and suggest that a particular histone modification is directly linked to these processes. Af17-mediated regulation of BP is largely, but not exclusively, the result of modulating ENaC, suggesting it has potential as a therapeutic target for the control of BP.

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Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule

Cited by 337 publications

References 30 publications

Genetics of arterial hypertension and hypotension

Genetics of arterial hypertension and hypotension

Serine-threonine kinase with-no-lysine 4 (WNK4) controls blood pressure via transient receptor potential canonical 3 (TRPC3) in the vasculature

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

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