NCC regulation by WNK signal cascade

Frontiers in Physiology

Physiology

Takayasu Mori¹  Koichiro Susa¹  Eisei Sohara¹  Shinichi Uchida² 

[1] Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;null;

关键词: pseudohypoaldosteronism type II;    WNK kinases;    OSR1;    SPAK;    NCC;    KLHL3;    CUL3;   

DOI  :  10.3389/fphys.2022.1081261

 received in 2022-10-27, accepted in 2022-12-14,  发布年份 2023

来源: Frontiers

【 摘 要 】

With-no-lysine (K) (WNK) kinases have been identified as the causal genes for pseudohypoaldosteronism type II (PHAII), a rare hereditary hypertension condition characterized by hyperkalemia, hyperchloremic metabolic acidosis, and thiazide-hypersensitivity. We thought that clarifying the link between WNK and NaCl cotransporter (NCC) would bring us new mechanism(s) of NCC regulation. For the first time, we were able to produce a knock-in mouse model of PHAII and anti-phosphorylated NCC antibodies against the putative NCC phosphorylation sites and discover that constitutive activation of NCC and increased phosphorylation of NCC are the primary pathogenesis of the disease in vivo. We have since demonstrated that this regulatory mechanism is mediated by the kinases oxidative stress-response protein 1 (OSR1) and STE20/SPS1-related proline/alanine-rich kinase (SPAK) (WNK–OSR1/SPAK-NCC signaling cascade) and that the signaling is not only important in the pathological condition of PHAII but also plays a crucial physiological role in the regulation of NCC.

【 授权许可】

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Copyright © 2023 Uchida, Mori, Susa and Sohara.