Pathogenesis of pseudohypoaldosteronism type 2 by WNK1 mutations

  title={Pathogenesis of pseudohypoaldosteronism type 2 by WNK1 mutations},
  author={Sonia Bergaya and Emmanuelle Vidal-Petiot and Xavier Jeunema{\^i}tre and Juliette Hadchouel},
  journal={Current Opinion in Nephrology and Hypertension},
Purpose of reviewPseudohypoaldosteronism type 2 (PHA2) is a rare autosomal dominant form of human arterial hypertension, associated with hyperkalemia and hyperchloremic metabolic acidosis. WNK1 and WNK4 are two of the genes mutated in PHA2 patients. This review focuses on the mechanisms by which deletions of the first intron of WNK1 found in PHA2 patients trigger the disease. Recent findingsThe WNK1 gene gives rise to a ubiquitous kinase (L-WNK1) and to a shorter kinase-defective isoform, KS… 

SPAK Deficiency Corrects Pseudohypoaldosteronism II Caused by WNK4 Mutation

SPAK may be a therapeutic target for disorders with salt-sensitive hypertension related to WNK4 activation and activation of SPAK-NCC plays the dominant role in PHA II.

Clinical features and genetic findings in Chinese children with distal renal tubular acidosis.

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  • 2018
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WNK-SPAK/OSR1-NCC kinase signaling pathway as a novel target for the treatment of salt-sensitive hypertension

An overview of the currently reported molecular inhibitors of the WNK-SPAK/OSR1-NCC pathway is provided and their potential as treatment options for Gordon’s syndrome are discussed.

Inherited forms of mineralocorticoid hypertension.

Disorders of aldosterone synthesis, secretion, and cellular function

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    Current opinion in pediatrics
  • 2014
Purpose of review The purpose of this review is to describe the renin–angiotensin–aldosterone system and its regulatory control of sodium, potassium, chloride, hydrogen ion, and water homeostasis

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I-1 is a DCT-enriched gene product that controls arterial BP, possibly through regulation of NCC activity.

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It is shown that apoptosis signal-regulating kinase 3 (ASK3) is predominantly expressed in the kidney and alters its kinase activity bidirectionally in response to osmotic stress and that it has a role in the control of blood pressure as an upstream suppressor of the WNK1-SPAK/OSR1 signalling pathway.



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Downregulation of NCC and NKCC2 cotransporters by kidney-specific WNK1 revealed by gene disruption and transgenic mouse models.

It is reported that mice overexpressing KS-WNK1 in the kidney exhibited renal Na(+) wasting, elevated plasma levels of angiotensin II and aldosterone yet lower blood pressure relative to wild-type littermates, and this results have important implications to the pathogenesis of PHA2 with WNK1 mutations.

WNK4 regulates airway Na+ transport: study of familial hyperkalaemia and hypertension.

Mutant WNK4 increases Na+ transport in airways, and therefore it is regulated by wild-type W NK4, and this may be caused by a regulation of ENaC or a K+ channel.

Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms

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Deletion of WNK1 First Intron Results in Misregulation of Both Isoforms in Renal and Extrarenal Tissues

Using a transgenic mouse model, the first insight is provided into the molecular mechanisms of WNK1-induced familial hyperkalemic hypertension by finding that intron 1 deletion resulted in the overexpression of L- and KS-WNK1 in the distal convoluted tubule and ubiquitous ectopic KS-wnK1 expression.

The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex.

It is shown that WNK3, another member of the WNK kinase family expressed by distal tubule cells, interacts with WNK4 and WNK1 to regulate NCC in both human kidney cells and Xenopus oocytes, further supporting the W NK signaling complex hypothesis.

Spectrum of mutations in Gitelman syndrome.

Gitelman's syndrome (GS) is a rare, autosomal recessive, salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive NaCl cotransporter (NCC). Because 18 to

WNK1 affects surface expression of the ROMK potassium channel independent of WNK4.

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Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo.

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