RESUMEN
Maturation of the glomerular basement membrane (GBM) is essential for maintaining the integrity of the renal filtration barrier. Impaired maturation causes proteinuria and renal fibrosis in the type IV collagen disease Alport syndrome. This study evaluates the role of collagen receptors in maturation of the GBM, matrix accumulation and renal fibrosis by using mice deficient for discoidin domain receptor 1 (DDR1), integrin subunit α2 (ITGA2), and type IV collagen α3 (COL4A3). Loss of both collagen receptors DDR1 and integrin α2ß1 delays maturation of the GBM: due to a porous GBM filtration barrier high molecular weight proteinuria that more than doubles between day 60 and day 100. Thereafter, maturation of the GBM causes proteinuria to drop down to one tenth until day 200. Proteinuria and the porous GBM cause accumulation of glomerular and tubulointerstitial matrix, which both decrease significantly after GBM-maturation until day 250. In parallel, in a disease with impaired GBM-maturation such as Alport syndrome, loss of integrin α2ß1 positively delays renal fibrosis: COL4A3(-/-)/ITGA2(-/-) double knockouts exhibited reduced proteinuria and urea nitrogen compared to COL4A3(-/-)/ITGA2(+/-) and COL4A3(-/-)/ITGA2(+/+) mice. The double knockouts lived 20% longer and showed less glomerular and tubulointerstitial extracellular matrix deposition than the COL4A3(-/-) Alport mice with normal integrin α2ß1 expression. Electron microscopy illustrated improvements in the glomerular basement membrane structure. MMP2, MMP9, MMP12 and TIMP1 were expressed at significantly higher levels (compared to wild-type mice) in COL4A3(-/-)/ITGA2(+/+) Alport mice, but not in COL4A3(+/+)/ITGA2(-/-) mice. In conclusion, the collagen receptors DDR1 and integrin α2ß1 contribute to regulate GBM-maturation and to control matrix accumulation. As demonstrated in the type IV collagen disease Alport syndrome, glomerular cell-matrix interactions via collagen receptors play an important role in the progression of renal fibrosis.
Asunto(s)
Fibrosis/genética , Integrina alfa2beta1/genética , Glomérulos Renales/crecimiento & desarrollo , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Receptores Mitogénicos/biosíntesis , Animales , Receptores con Dominio Discoidina , Matriz Extracelular/genética , Matriz Extracelular/patología , Fibrosis/patología , Membrana Basal Glomerular/crecimiento & desarrollo , Membrana Basal Glomerular/metabolismo , Humanos , Integrina alfa2beta1/metabolismo , Riñón/patología , Glomérulos Renales/patología , Ratones , Ratones Noqueados , Nefritis Hereditaria/genética , Nefritis Hereditaria/patología , Receptores de Colágeno/genética , Receptores de Colágeno/metabolismoRESUMEN
LMX1B, a developmental LIM-homeodomain transcription factor, is widely expressed in vertebrate embryos, and it takes part in the development of diverse structures such as limbs, kidneys, eyes, brains, etc. LMX1B contributes to transcriptional regulation of glomerular basement membrane (GBM) collagen expression by podocytes. The normal function of podocytes and the normal morphology of GBM are very important to maintain the healthy renal filtration barrier. Recent discoveries find that the LMX1B gene is pivotal in glomus development and it is implicated in the dysfunction of the podocytes. Here, we review the signal transduction pathways of LMX1B and its role in the pathogenesis of glomerulosclerosis.