Deficiency of the Planar Cell Polarity Protein Vangl2 in Podocytes Affects Glomerular Morphogenesis and Increases Susceptibility to Injury

Abstract

The planar cell polarity (PCP) signaling pathway is crucial for tissue morphogenesis. Van Gogh-like protein 2 (Vangl2) is central in the PCP pathway; in mice, Vangl2 loss is embryonically lethal because of neural tube defects, and mutations in Vangl2 are associated with human neural tube defects. In the kidney, PCP signaling may be important for tubular morphogenesis and organization of glomerular epithelial cells (podocytes) along the glomerular basement membrane. Podocyte cell protrusions (foot processes) are critical for glomerular permselectivity; loss of foot process architecture results in proteinuria and FSGS. Previously, we showed a profound effect of PCP signaling on podocyte shape, actin rearrangement, cell motility, and nephrin endocytosis. To test our hypothesis that the PCP pathway is involved in glomerular development and function and circumvent lethality of the ubiquitous Vangl2 mutation in the Looptail mouse, we generated a mouse model with a podocyte-specific ablation of the Vangl2 gene. We report here that podocyte-specific deletion of Vangl2 leads to glomerular maturation defects in fetal kidneys. In adult mice, we detected significantly smaller glomeruli, but it did not affect glomerular permselectivity in aging animals. However, in the context of glomerular injury induced by injection of antiglomerular basement membrane antibody, deletion of Vangl2 resulted in exacerbation of injury and accelerated progression to chronic segmental and global glomerular sclerosis. Our results indicate that Vangl2 function in podocytes is important for glomerular development and protects against glomerular injury in adult animals. 26: 576-586, 201526: 576-586, . doi: 10.1681 Renal glomerular visceral epithelial cells (podocytes) are highly polarized cells with complex threedimensional architecture characterized by the presence of unique actin-based projections (foot processes [FPs]). 1 The FPs from neighboring podocytes form intercellular bridges, slit diaphragms, that are the only points of contact between adjacent cells and the base for the permselective filtration barrier, allowing small solutes to pass into the urinary space while retaining large proteins in the blood. 1 Slit diaphragm protein complexes are connected with the podocyte cytoskeleton by various adaptor proteins and serve as a signaling nexus to relay information from the FP surface to control podocyte structure. 2 The characteristic shape of podocytes is directly related to glomerular filtration. Mutations in proteins that link slit diaphragms and the cytoskeleton (e.g., a-actinin-4 and CD2-associated protein) 3,4 or regulators of actin polymerization and organization (e.g., Inverted Formin-2, Myosin 1e, Rho GDP-Dissociation Inhibitor 1, and Cdc42) 5-9 give rise to glomerular dysfunction, such as proteinuria, J Am Soc Nephrol

Planar cell polarity genes Celsr1 and Vangl2 are necessary for kidney growth, differentiation, and rostrocaudal patterning

“…We reported that although the initiation of the ureteric bud was normal in homozygous mutant Vangl2 embryos, subsequent ureteric bud branching within the metanephros was defective 14 . Furthermore, we 14 and others 15 found that these kidneys contained poorly differentiated glomeruli. These defects correlate with reported sites of Vangl2 mRNA expression, including podocytes and ureteric bud epithelia 14, 16.…”

Planar Cell Polarity Pathway in Kidney Development and Function

“…Podocyte-specific Cre-LoxPmediated abrogation of Vangl2 resulted in a similar glomerular developmental delay phenotype [124]. However, by the end of nephrogenesis at P14, a developmental "catch-up" seems to have occurred so that the glomeruli in either mutant or control mice looked similar, though mutant glomeruli were smaller and had fewer podocytes.…”

“…However, by the end of nephrogenesis at P14, a developmental "catch-up" seems to have occurred so that the glomeruli in either mutant or control mice looked similar, though mutant glomeruli were smaller and had fewer podocytes. Podocyte-specific loss of Vangl2 did not affect filtration function in adult kidneys: protein excretion at 12 months was comparable in both genotypes [124]. Yet, in the context of glomerular injury induced by heterologous anti-glomerular basement membrane (anti-GBM) antibody, the extent of injury was heightened and glomerular recovery was impaired in mutant versus control animals.…”

Recent advances of animal model of focal segmental glomerulosclerosis

“…In adult mice, significantly smaller glomeruli were detected, but it did not affect glomerular permselectivity in aging animals. In the context of glomerular injury induced by injection of anti-glomerular basement membrane antibody, deletion of Vangl2 resulted in injury exacerbation and accelerated progression to chronic segmental and global glomerular sclerosis [72,73] (Table 2; Fig. 1).…”