title: MAGI-2 scaffold protein is critical for kidney barrier function.
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.
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: Minna D
authors.initials: MD
authors.lastname: Balbas
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, CA 94143;
authors.forename: Michael R
authors.initials: MR
authors.lastname: Burgess
authors.affiliation: Department of Pathology, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, and.
authors.forename: Rajmohan
authors.initials: R
authors.lastname: Murali
authors.affiliation: Human Oncology and Pathogenesis Program.
authors.forename: John
authors.initials: J
authors.lastname: Wongvipat
authors.affiliation: Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Skaggs
authors.affiliation: Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Mundel
authors.affiliation: Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Astrid
authors.initials: A
authors.lastname: Weins
authors.affiliation: Human Oncology and Pathogenesis Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; sawyersc@mskcc.org.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D051528:Guanylate Kinases / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007678:Kidney Glomerulus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C498782:Sh3kbp1 protein, mouse; C113267:nephrin; D051528:Guanylate Kinases; C405684:Magi2 protein, mouse
keywords: MAGI-2/S-SCAM; glomerulosclerosis