Impaired degradation of medullary WNK4 in the kidneys of KLHL2 knockout mice.

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 WNKs in 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 WNK4 in vivo ; however, its function might be different from that of KLHL3 because KLHL2 mainly localized in medulla. [ABSTRACT FROM AUTHOR]