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

TL;DR

Knocking down the long isoform of WNK1 kinase in mice reduces kidney inflammation and injury in a model of glomerulonephritis.

Contribution

This study identifies L-WNK1 as a novel contributor to glomerulonephritis pathophysiology through its effects on glomerular cells and parietal epithelial cell migration.

Findings

Knock-down of L-WNK1 mitigates RPGN in mice.

L-WNK1 inhibition impairs parietal epithelial cell migration in vitro.

L-WNK1 is upregulated in glomerular cells during RPGN.

Abstract

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.

The online version contains supplementary material available at 10.1038/s41598-026-36715-8.

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