Publications | Role of KLHL3 and dietary K + in regulating KS-WNK1 expression

The physiological role of the shorter isoform of WNK1 that is exclusively expressed in the kidney (KS-WNK1), with particular abundance in the distal convoluted tubule, remains elusive. KS-WNK1 despite lacking the kinase domain, is nevertheless capable of stimulating the NaCl cotransporter (NCC), apparently through activation of WNK4. It has recently been shown that a less severe form of the Familial Hyperkalemic Hypertension featuring only hyperkalemia is caused by missense mutations in the WNK1 acidic domain that preferentially affect CUL3-KLHL3 E3-induced degradation of KS-WNK1, rather than that of the full-length WNK1 (L-WNK1). Here we show that L-WNK1 is indeed less impacted by the CUL3-KLHL3 E3 ligase complex compared to KS-WNK1. We demonstrate that the unique 30 amino acid amino N-terminal fragment of KS-WNK1 is essential for its activating effect on NCC and recognition by KLHL3. We identify specific amino acid residues in this region critical for the functional effect of KS-WNK1 and KLHL3 sensitivity. To further explore this, we generated KLHL3-R528H knock-in mice that mimic human mutations causing Familial Hyperkalemic Hypertension. These mice revealed that the KLHL3 mutation specifically increased expression of KS-WNK1 in the kidney. We also observed that in wild type mice, expression of KS-WNK1 is only detectable after exposure to low potassium diet. These findings provide new insights into the regulation and function of KS-WNK1 by the CUL3-KLHL3 complex in DCT and indicate that this pathway is regulated by dietary K+ levels.

Principal Investigator(s):

Author(s):
Ostrosky-Frid M, Chavez-Canales M, Zhang J, Andrukova O, Argaiz ER, Lerdo de Tejada F, Murillo-de-Ozores AR, Sanchez-Navarro A, Rojas-Vega L, Bobadilla NA, Vazquez N, Castaneda-Bueno M, Alessi DR, Gamba G

PubMed:
33682442
Citation:
Ostrosky-Frid M, Chavez-Canales M, Zhang J, Andrukova O, Argaiz ER, Lerdo de Tejada F, Murillo-de-Ozores AR, Sanchez-Navarro A, Rojas-Vega L, Bobadilla NA, Vazquez N, Castaneda-Bueno M, Alessi DR, Gamba G
Am J Physiol Renal Physiol
2021
Mar
doi:
10.1152/ajprenal.00575.2020
PMID: 33682442