The WNK signaling pathway and salt-sensitive hypertension.
Hypertension
NaCl cotransporter
Salt sensitivity
WNK signaling
Journal
Hypertension research : official journal of the Japanese Society of Hypertension
ISSN: 1348-4214
Titre abrégé: Hypertens Res
Pays: England
ID NLM: 9307690
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
02
03
2020
accepted:
11
03
2020
revised:
11
03
2020
pubmed:
15
4
2020
medline:
17
8
2021
entrez:
15
4
2020
Statut:
ppublish
Résumé
The distal nephron of the kidney has a central role in sodium and fluid homeostasis, and disruption of this homeostasis due to mutations of with-no-lysine kinase 1 (WNK1), WNK4, Kelch-like 3 (KLHL3), or Cullin 3 (CUL3) causes pseudohypoaldosteronism type II (PHAII), an inherited hypertensive disease. WNK1 and WNK4 activate the NaCl cotransporter (NCC) at the distal convoluted tubule through oxidative stress-responsive gene 1 (OSR1)/Ste20-related proline-alanine-rich kinase (SPAK), constituting the WNK-OSR1/SPAK-NCC phosphorylation cascade. The level of WNK protein is regulated through degradation by the CUL3-KLHL3 E3 ligase complex. In the normal state, the activity of WNK signaling in the kidney is physiologically regulated by sodium intake to maintain sodium homeostasis in the body. In patients with PHAII, however, because of the defective degradation of WNK kinases, NCC is constitutively active and not properly suppressed by a high salt diet, leading to abnormally increased salt reabsorption and salt-sensitive hypertension. Importantly, recent studies have demonstrated that potassium intake, insulin, and TNFα are also physiological regulators of WNK signaling, suggesting that they contribute to the salt-sensitive hypertension associated with a low potassium diet, metabolic syndrome, and chronic kidney disease, respectively. Moreover, emerging evidence suggests that WNK signaling also has some unique roles in metabolic, cardiovascular, and immunological organs. Here, we review the recent literature and discuss the molecular mechanisms of the WNK signaling pathway and its potential as a therapeutic target.
Identifiants
pubmed: 32286498
doi: 10.1038/s41440-020-0437-x
pii: 10.1038/s41440-020-0437-x
doi:
Substances chimiques
Sodium Chloride, Dietary
0
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
733-743Références
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