title: 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.
authors.affiliation: Departments of Medicine and Physiology, McGill University and McGill University Health Centre, Montreal, Quebec, Canada; and.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Rocque
authors.affiliation: Departments of Medicine and Physiology, McGill University and McGill University Health Centre, Montreal, Quebec, Canada; and.
authors.forename: Sima
authors.initials: S
authors.lastname: Babayeva
authors.affiliation: Departments of Medicine and Physiology, McGill University and McGill University Health Centre, Montreal, Quebec, Canada; and.
authors.forename: Jane
authors.initials: J
authors.lastname: Li
authors.affiliation: Departments of Human Genetics and Complex Traits Group, McGill University, Montreal, Quebec, Canada.
authors.forename: Vicki
authors.initials: V
authors.lastname: Leung
authors.affiliation: Departments of Medicine and Physiology, McGill University and McGill University Health Centre, Montreal, Quebec, Canada; and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Nezvitsky
authors.affiliation: Departments of Medicine and Physiology, McGill University and McGill University Health Centre, Montreal, Quebec, Canada; and.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Cybulsky
authors.affiliation: Complex Traits Group, McGill University, Montreal, Quebec, Canada Biochemistry and.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
authors.affiliation: Departments of Medicine and Physiology, McGill University and McGill University Health Centre, Montreal, Quebec, Canada; and elena.torban@mcgill.ca.
authors.forename: Elena
authors.initials: E
authors.lastname: Torban
mesh_terms: D000818:Animals; D016764:Cell Polarity; D005260:Female; D007678:Kidney Glomerulus / Q000196:embryology* / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism
chemical_list: C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins
keywords: genetics and development; glomerular disease; kidney development