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L-WNK1 and KS-WNK1, two key regulators of ion transport in the distal nephron

Over the last 15 years, numerous studies have led to the identification of the WNK1 kinase as a switch between K+ secretion and Na+ reabsorption in response to aldosterone in the distal nephron. However, a few questions remain unanswered:

(1) which are the pathways activated by L-WNK1, the catalytically active and ubiquitous isoform, in the distal nephron? Several studies have shown that L-WNK1 activates SPAK by phosphorylation, which in turns activates the NCC co-transporter. However, several data suggest that L-WNK1 can act in a SPAK-independent manner.

(2) what is the role of KS-WNK1, the kinase-deficient WNK1 isoform, expressed specifically in the distal nephron? In vitro studies have suggested that KS-WNK1 acts only as a dominant-negative of L-WNK1 but the characterization of a mouse model of KS-WNK1 inactivation led us to believe that KS-WNK1 could activate different signalling pathways, independently of L-WNK1.