RESUMEN
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.
Asunto(s)
Polaridad Celular , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Glomérulos Renales/metabolismo , Proteínas de la Membrana/metabolismo , Nefrosis Lipoidea/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Podocitos/metabolismo , Adulto , Animales , Estudios de Casos y Controles , Células Cultivadas , Modelos Animales de Enfermedad , Activación Enzimática , Femenino , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/fisiopatología , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Glomérulos Renales/patología , Glomérulos Renales/fisiopatología , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Nefrosis Lipoidea/genética , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/fisiopatología , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Podocitos/patología , Transducción de Señal , Adulto JovenRESUMEN
The mammalian kidney contains nephrons comprising glomeruli and tubules joined to ureteric bud-derived collecting ducts. It has a characteristic bean-like shape, with near-complete rostrocaudal symmetry around the hilum. Here we show that Celsr1, a planar cell polarity (PCP) gene implicated in neural tube morphogenesis, is required for ureteric tree growth in early development and later in gestation prevents tubule overgrowth. We also found an interaction between Celsr1 and Vangl2 (another PCP gene) in ureteric tree growth, most marked in the caudal compartment of the kidneys from compound heterozygous mutant mice with a stunted rump. Furthermore, these genes together are required for the maturation of glomeruli. Interestingly, we demonstrated patients with CELSR1 mutations and spina bifida can have significant renal malformations. Thus, PCP genes are important in mammalian kidney development and have an unexpected role in rostrocaudal patterning during organogenesis.