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Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):14876-81. doi: 10.1073/pnas.1417297111. Epub 2014 Sep 30.

MAGI-2 scaffold protein is critical for kidney barrier function.

Author information

1
Human Oncology and Pathogenesis Program.
2
Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, CA 94143;
3
Department of Pathology, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, and.
4
Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
5
Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114; and.
6
Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115.
7
Human Oncology and Pathogenesis Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; sawyersc@mskcc.org.

Abstract

MAGUK Inverted 2 (MAGI-2) is a PTEN-interacting scaffold protein implicated in cancer on the basis of rare, recurrent genomic translocations and deletions in various tumors. In the renal glomerulus, MAGI-2 is exclusively expressed in podocytes, specialized cells forming part of the glomerular filter, where it interacts with the slit diaphragm protein nephrin. To further explore MAGI-2 function, we generated Magi-2-KO mice through homologous recombination by targeting an exon common to all three alternative splice variants. Magi-2 null mice presented with progressive proteinuria as early as 2 wk postnatally, which coincided with loss of nephrin expression in the glomeruli. Magi-2-null kidneys revealed diffuse podocyte foot process effacement and focal podocyte hypertrophy by 3 wk of age, as well as progressive podocyte loss. By 5.5 wk, coinciding with a near-complete loss of podocytes, Magi-2-null mice developed diffuse glomerular extracapillary epithelial cell proliferations, and died of renal failure by 3 mo of age. As confirmed by immunohistochemical analysis, the proliferative cell populations in glomerular lesions were exclusively composed of activated parietal epithelial cells (PECs). Our results reveal that MAGI-2 is required for the integrity of the kidney filter and podocyte survival. Moreover, we demonstrate that PECs can be activated to form glomerular lesions resembling a noninflammatory glomerulopathy with extensive extracapillary proliferation, sometimes resembling crescents, following rapid and severe podocyte loss.

KEYWORDS:

MAGI-2/S-SCAM; glomerulosclerosis

PMID:
25271328
PMCID:
PMC4205655
DOI:
10.1073/pnas.1417297111
[Indexed for MEDLINE]
Free PMC Article

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