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

Eugenia Papakrivopoulou,Charlotte H Dean,Elisavet Vasilopoulou,David A Long,Clemens D Cohen,Karen L Price,Deborah J Henderson,Alan D Salama,Kathryn E White,Maria Kolatsi‐Joannou,Maja T Lindenmeyer,Adrian S Woolf,Hortensja Ł Brzóska,Sabrina Pacheco

doi:10.1002/path.5158

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.

Highlights

Van Gogh-like 2 (Vangl2) regulates planar cell polarity (PCP), controlling orientation and alignment of epithelial cells within tissues [1]
We examined the specificity of Cre recombination by breeding PodCre+ mice with R26R-EYFP mice, which have a loxP-flanked STOP sequence followed by the enhanced yellow fluorescent protein gene (EYFP) inserted into the Gt(ROSA)26Sor locus
Targeted genetic downregulation of Vangl2 in podocytes enhanced the severity of both accelerated nephrotoxic nephritis (NTN) and LPS-induced glomerular damage

Summary

Introduction

Van Gogh-like 2 (Vangl2) regulates planar cell polarity (PCP), controlling orientation and alignment of epithelial cells within tissues [1]. Vangl is expressed in epithelial podocytes in forming glomeruli, the blood ultrafiltration units, and in nephron and collecting duct tubules [7,8]. Homozygous Loop-tail mice with Vangl2Lp point mutations have malformed kidneys with a paucity of collecting ducts and dysmorphic glomeruli [9,10]. Vangl2Lp/+ kidneys develop normally, compound heterozygotes harbouring Vangl2Lp and a point mutation in another PCP gene, Cadherin EGF LAG seven-pass G-type receptor 1 (Celsr1), have branching malformations [11]. PCP is implicated in acquired kidney disease. Glomerular Vangl transcripts increased 48 h after the initiation of kidney injury by nephrotoxic nephritis (NTN), a progressive disease model, and NTN is more severe in mice with podocyte-specific Vangl deletion [8]

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