α-Actinin-4 Is Required for Normal Podocyte Adhesion
Dandapani, Savita V.
Matthews, Benjamin D.
Kolb, Robert J.
Gerszten, Robert E.
Ingber, Donald E.
Pollak, Martin R.
MetadataShow full item record
CitationDandapani, Savita V., Hikaru Sugimoto, Benjamin D. Matthews, Robert J. Kolb, Sumita Sinha, Robert E. Gerszten, Jing Zhou, Donald E. Ingber, Raghu Kalluri, and Martin R. Pollak. 2006. “α-Actinin-4 Is Required for Normal Podocyte Adhesion.” Journal of Biological Chemistry 282 (1): 467–77. https://doi.org/10.1074/jbc.m605024200.
AbstractMutations in the alpha-actinin-4 gene ACTN4 cause an autosomal dominant human kidney disease. Mice deficient in alpha-actinin-4 develop a recessive phenotype characterized by kidney failure, proteinuria, glomerulosclerosis, and retraction of glomerular podocyte foot processes. However, the mechanism by which alpha-actinin-4 deficiency leads to glomerular disease has not been defined. Here, we examined the effect of alpha-actinin-4 deficiency on the adhesive properties of podocytes in vivo and in a cell culture system. In alpha-actinin-4-deficient mice, we observed a decrease in the number of podocytes per glomerulus compared with wild-type mice as well as the presence of podocyte markers in the urine. Podocyte cell lines generated from alpha-actinin-4-deficient mice were less adherent than wild-type cells to glomerular basement membrane (GBM) components collagen IV and laminin 10 and 11. We also observed markedly reduced adhesion of alpha-actinin-4-deficient podocytes under increasing shear stresses. This adhesion deficit was restored by transfecting cells with alpha-actinin-4-GFP. We tested the strength of the integrin receptor-mediated linkages to the cytoskeleton by applying force to microbeads bound to integrin using magnetic pulling cytometry. Beads bound to alpha-actinin-4-deficient podocytes showed greater displacement in response to an applied force than those bound to wild-type cells. Consistent with integrin-dependent alpha-actinin-4-mediated adhesion, phosphorylation of beta 1-integrins on alpha-actinin-4-deficient podocytes is reduced. We rescued the phosphorylation deficit by transfecting alpha-actinin-4 into a-actinin-4-deficient podocytes. These results suggest that alpha-actinin-4 interacts with integrins and strengthens the podocyte-GBM interaction thereby stabilizing glomerular architecture and preventing disease.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41467422
- FAS Scholarly Articles