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

Abstract

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 the 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. In addition, by interrogating microarray data from two cohorts of renal patients, we report increased VANGL2 transcript levels in the 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. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors

“…Surprisingly, heterozygous loss of Vangl2, through the Vangl2 S464N mutation, is sufficient to reduce biliary scarring, suggesting that this system requires tight regulation. Emerging data from other chronically diseased tissues indicate that Wnt-PCP signalling can play a role in the establishment and maintenance of scarring and deposition of the extracellular matrix 20,53,69,70 ; here we show that Wnt-PCP is also involved in the formation of biliary scars in the adult liver.…”

Role of a RhoA/ROCK-Dependent Pathway on Renal Connexin43 Regulation in the Angiotensin II-Induced Renal Damage

“…Indeed, downregulation of Vangl2 increased the activity of matrix metalloproteinase-9 (MMP9). MMP9 has previously been shown to be produced by podocytes and it is altered in a number of glomerular diseases, supporting the conclusion that Vangl2 modulates glomerular injury by stopping MMP9 production [48].Therefore, it is possible that TGF-β, lymph angiogenesis and/or Vangl2 could be involved in the development of renal fibrosis and inflammation, thus it could be a key factor in the irreversibility of kidney damage; consequently, additional studies are required to address and demonstrate the involvement of these factors in the reversibility/irreversibility of renal damage, independent of the initial stimulus.…”

“…In the kidney, lymph angiogenesis occurs after proteinuria is established and prior to collagen deposition, fibrosis and macrophage infiltration, whereas angiotensin converting enzyme (ACE) inhibition significantly prevents this new lymph vessel formation [45,47]. Papakrivopoulou et al, by analyzing mouse models of irreversible and reversible glomerular injury, described that Van Goghlike 2 (Vangl2), a protein that regulates planar cell polarity (PCP) is implicated in acquired kidney disease by modulating tissue remodeling that includes cytoskeletal rearrangements affecting cell morphology or changes in inflammation [48]. Indeed, downregulation of Vangl2 increased the activity of matrix metalloproteinase-9 (MMP9).…”

The Role of Wnt Signalling in Chronic Kidney Disease (CKD)

“…Conserved PCP proteins have further been reported to influence the function of cilia, hence why mutations in PCP genes have been shown to cause ciliopathies ranging from PKD to rarer genetic disorders like MGS, Bardet-Bieldl syndrome and NPHP [80]. It has been shown that Vangl2 is normally expressed in epithelial podocytes that regulate normal differentiation, which later induces the formation of the glomeruli, nephron tubules and collecting duct tubules [81]. Point mutation of Vangl2 in homozygous loop-tail (Lp) mice resulted in malformed kidneys alongside dysmorphic glomeruli [81].…”