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

Mauricio Ostrosky-Frid, Maria Chavez-Canales, Jinwei Zhang, Olena Andrukova, Eduardo R. Argaiz, Fernando Lerdo de Tejada, Adrián R. Murillo-de-Ozores, Andrea Sanchez-Navarro, Lorena Rojas-Vega, Norma A. Bobadilla, Norma Vazquez, Maria Castaneda-Bueno, Dario R. Alessi, Gerardo Gamba (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

Abstract

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, apparently through activation of WNK4. It has recently been shown that a less severe form of familial hyperkalemic hypertension featuring only hyperkalemia is caused by missense mutations in the WNK1 acidic domain that preferentially affect cullin 3 (CUL3)-Kelch-like protein 3 (KLHL3) E3-induced degradation of KS-WNK1 rather than that of full-length WNK1. Here, we show that full-length WNK1 is indeed less impacted by the CUL3-KLHL3 E3 ligase complex compared with KSWNK1. We demonstrated that the unique 30-amino acid amino NH2-terminal fragment of KS-WNK1 is essential for its activating effect on the NaCl cotransporter and recognition by KLHL3. We identified 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 knockin 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, the expression of KS-WNK1 was only detectable after exposure to a low-K+ diet. These findings provide new insights into the regulation and function of KS-WNK1 by the CUL3-KLHL3 complex in the distal convoluted tubule and indicate that this pathway is regulated by dietary K+ levels.

Original languageEnglish
JournalAmerican Journal of Physiology: Renal Physiology
Early online date8 Mar 2021
DOIs
Publication statusE-pub ahead of print - 8 Mar 2021

Keywords

  • WNK4
  • Distal convoluted tubule
  • Hypertension
  • SPAK
  • salt transport

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