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J. Biol. Chem., Vol. 282, Issue 1, 467-477, January 5, 2007

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-Actinin-4 Is Required for Normal Podocyte Adhesion^*

Savita V. Dandapani, Hikaru Sugimoto^¶, Benjamin D. Matthews^||**, Robert J. Kolb, Sumita Sinha, Robert E. Gerszten, Jing Zhou, Donald E. Ingber^**, Raghu Kalluri^¶, and Martin R. Pollak, An Established Investigator of the American Heart Association¹

From the Department of Genetics, Harvard Medical School, Boston, Massachusetts, the Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, the ^¶Division of Matrix Biology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, the ^||Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, the ^**Vascular Biology Program, Departments of Pathology and Surgery, Children's Hospital, Boston, Massachusetts 02115, and the Center for Immunology and Inflammatory Diseases, and Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129

Mutations in the -actinin-4 gene ACTN4 cause an autosomal dominant human kidney disease. Mice deficient in -actinin-4 develop a recessive phenotype characterized by kidney failure, proteinuria, glomerulosclerosis, and retraction of glomerular podocyte foot processes. However, the mechanism by which -actinin-4 deficiency leads to glomerular disease has not been defined. Here, we examined the effect of -actinin-4 deficiency on the adhesive properties of podocytes in vivo and in a cell culture system. In -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 -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 -actinin-4-deficient podocytes under increasing shear stresses. This adhesion deficit was restored by transfecting cells with -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-actinin-4-deficient podocytes showed greater displacement in response to an applied force than those bound to wild-type cells. Consistent with integrin-dependent -actinin-4-mediated adhesion, phosphorylation of 1-integrins on -actinin-4-deficient podocytes is reduced. We rescued the phosphorylation deficit by transfecting -actinin-4 into -actinin-4-deficient podocytes. These results suggest that -actinin-4 interacts with integrins and strengthens the podocyte-GBM interaction thereby stabilizing glomerular architecture and preventing disease.

Received for publication, May 25, 2006 , and in revised form, October 24, 2006.

^* This work was supported in part by Grants DK066017 (to M. P. and R. G.), HL65584 (to R. G.), DK55001 (to R. K.), and CA45548 (to D. I.) from the National Institutes of Health, Grant N00014-01-1-0782 (to D. I.) from the Department of Defense, funds from the Center for Matrix Biology at the Beth Israel Deaconess Medical Center (to R. K.), the Stop and Shop Pediatric Brain Research Fund (to H. S.), a predoctoral fellowship from the American Heart Association (to S. D.), and a National Institutes of Health-Medical Scientist Training Program Grant (to S. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5 and Videos 1A-1C.

¹ To whom correspondence should be addressed: 4 Blackfan Circle, Boston, MA 02115. Tel.: 617-525-5840; Fax: 617-525-5841; E-mail: mpollak{at}rics.bwh.harvard.edu.

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