Vangl2, a planar cell polarity molecule, is implicated in irreversible and reversible kidney glomerular injury

Planar cell polarity (PCP) pathways control the orientation and alignment of epithelial cells

within tissues. Van Gogh-like 2 (Vangl2) is a key PCP protein that is required for normal

differentiation of kidney glomeruli and tubules. Vangl2 has also been implicated in

modifying the course of acquired glomerular disease and here we further explored how

Vangl2 impacts on glomerular pathobiology in this context. Targeted genetic deletion of

Vangl2 in mouse glomerular epithelial podocytes enhanced the severity of not only

irreversible accelerated nephrotoxic nephritis but also lipopolysaccharide-induced

reversible glomerular damage. In each proteinuric model, genetic deletion of Vangl2 in

podocytes was associated with an increased ratio of active-MMP9 to inactive MMP9, an

enzyme involved in tissue remodelling. Additionally, by interrogating microarray data from

two cohorts of renal patients, we report increased VANGL2 transcript levels in glomeruli of

individuals with focal segmental glomerulosclerosis, suggesting that the molecule may also

be involved in certain human glomerular diseases. These observations support the

conclusion that Vangl2 modulates glomerular injury, at least in part by acting as a brake on

MMP9, a potentially harmful endogenous enzyme.