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

Biochem Biophys Res Commun. 2017 May 27;487(2):368-374. doi: 10.1016/j.bbrc.2017.04.068. Epub 2017 Apr 14.


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.

Keywords: KLHL2; Pseudohypoaldosteronism type II; WNK4.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Down-Regulation / physiology
  • Kidney / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microfilament Proteins / metabolism*
  • Nerve Tissue Proteins / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • Tissue Distribution
  • Ubiquitination / physiology*


  • Adaptor Proteins, Signal Transducing
  • KLHL3 protein, mouse
  • Klhl2 protein, mouse
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Prkwnk4 protein, mouse
  • Protein Serine-Threonine Kinases