Impaired degradation of medullary WNK4 in the kidneys of KLHL2 knockout mice.
Impaired degradation of medullary WNK4 in the kidneys of KLHL2 knockout mice.
复制标题
DOI：
10.1016/j.bbrc.2017.04.068
复制
发表时间：
2017-05
影响因子：
3.1
通讯作者：
Y. Kasagi;Daiei Takahashi;Tomomi Aida;H. Nishida;Naohiro Nomura;M. Zeniya;Takayasu Mori;Emi Sasaki-Emi-Sas
中科院分区：
文献类型：
--
作者：
Y. Kasagi;Daiei Takahashi;Tomomi Aida;H. Nishida;Naohiro Nomura;M. Zeniya;Takayasu Mori;Emi Sasaki-Emi-Sas
无赖氨酸激酶1 （WNK1）、WNK4、kelch样3 （KLHL3）和Cullin3 （CUL3）基因突变被确定为遗传性高血压病假醛固酮减少症II型（PHAII）的原因。正常情况下，KLHL3/CUL3泛素连接酶复合物降解wnk。在PHAII中，由于泛素化受损，KLHL3和WNK4之间相互作用的丧失增加了WNKs的水平，导致肾远曲小管（DCT）中WNK-OSR1/SPAK-NCC级联的异常过度激活。据报道，与KLHL3高度同源的KLHL2在体外可泛素化并降解WNKsin。在PHAII患者中尚未报道KLHL2突变，这表明KLHL2在肾脏中发挥的生理作用与KLHL3不同。为了研究KLHL2在肾脏中的生理作用，我们制造了KLHL2−/−小鼠。KLHL2−/−小鼠没有表现出OSR1/SPAK-NCC级联磷酸化增加和phaii样表型。与皮层相比，KLHL2主要在髓质中表达。因此，在KLHL2−/−小鼠肾脏中，髓质WNK4蛋白水平显著升高。在体内，KLHL2确实是wnk4的生理调节因子；但其功能可能与KLHL3不同，因为KLHL2主要定位于髓质。
Mutations in the with-no-lysine kinase 1 (WNK1),WNK4, Kelch-like 3 (KLHL3), and Cullin3 (CUL3) genes were identified as being responsible for hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII). Normally, the KLHL3/CUL3 ubiquitin ligase complex degrades WNKs. In PHAII, the loss of interaction between KLHL3 and WNK4 increases levels of WNKs because of impaired ubiquitination, leading to abnormal over-activation of the WNK-OSR1/SPAK-NCC cascade in the kidney's distal convoluted tubules (DCT). KLHL2, which is highly homologous to KLHL3, was reported to ubiquitinate and degrade WNKsin vitro. Mutations in KLHL2 have not been reported in patients with PHAII, suggesting that KLHL2 plays a different physiological role than that played by KLHL3 in the kidney. To investigate the physiological roles of KLHL2 in the kidney, we generated KLHL2−/−mice. KLHL2−/−mice did not exhibit increased phosphorylation of the OSR1/SPAK-NCC cascade and PHAII-like phenotype. KLHL2 was predominantly expressed in the medulla compared with the cortex. Accordingly, medullary WNK4 protein levels were significantly increased in the kidneys of KLHL2−/−mice. KLHL2 is indeed a physiological regulator of WNK4in vivo; however, its function might be different from that of KLHL3 because KLHL2 mainly localized in medulla.