Knock-down of the long isoform of the WNK1 kinase mitigates the anti-glomerular basement membrane glomerulonephritis in mice

The roles of the long isoform of the With No Lysine (K) 1 (L-WNK1) kinase have been mainly studied in the distal renal tubule, where it participates in sodium and chloride homeostasis. Yet, little is known about its role in its predominant expression site within the kidney, i.e. the glomerulus. We chose to study the consequences of L-WNK1 inhibition in a mouse model of rapidly progressive glomerulonephritis (RPGN), combining podocyte injury and parietal epithelial cell (PEC) activation. We show that L-WNK1 expression is upregulated in glomerular cells during RPGN in mice. A 50% reduction in L-WNK1 expression mitigates experimental nephrotoxic serum-induced RPGN in mice. Given that L-WNK1 is strongly expressed in podocytes, which play an important role in RPGN pathogenesis, we then studied a model of podocyte-specific knockdown of WNK1. Even if we could observe some changes in NTS-induced RPGN following this knock-down, the effects are not as marked as in the global inhibition model. These data suggest that L-WNK1 plays an important role in other glomerular cell types. Accordingly, we show in vitro that the inhibition of L-WNK1 activity impairs PECs migration. These results suggest that L-WNK1 could represent a new player in the pathophysiology of RPGN.