Uchida Shinichi, Mori Takayasu, Susa Koichiro, Sohara Eisei
Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Front Physiol. 2023 Jan 4;13:1081261. doi: 10.3389/fphys.2022.1081261. eCollection 2022.
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 . 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.
无赖氨酸（K）（WNK）激酶已被确定为II型假性醛固酮增多症（PHAII）的致病基因，PHAII是一种罕见的遗传性高血压疾病，其特征为高钾血症、高氯性代谢性酸中毒和噻嗪类药物超敏反应。我们认为，阐明WNK与氯化钠协同转运蛋白（NCC）之间的联系将为我们带来NCC调节的新机制。我们首次构建了PHAII基因敲入小鼠模型，并针对假定的NCC磷酸化位点制备了抗磷酸化NCC抗体，发现NCC的组成性激活和NCC磷酸化增加是该疾病的主要发病机制。此后我们证明，这种调节机制由激酶氧化应激反应蛋白1（OSR1）和STE20/SPS1相关富含脯氨酸/丙氨酸激酶（SPAK）介导（WNK-OSR1/SPAK-NCC信号级联），并且该信号传导不仅在PHAII的病理状态中起重要作用，而且在NCC的调节中也发挥关键的生理作用。
