MAGI-2 scaffold protein is critical for kidney barrier function

被引:34
作者
Balbas, Minna D. [1 ]
Burgess, Michael R. [5 ]
Murali, Rajmohan [2 ,3 ]
Wongvipat, John [1 ]
Skaggs, Brian J. [6 ]
Mundel, Peter [7 ]
Weins, Astrid [8 ]
Sawyers, Charles L. [1 ,4 ]
机构
[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA
[2] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA
[3] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, New York, NY 10021 USA
[4] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10021 USA
[5] Univ Calif San Francisco, Dept Med, Div Hematol & Oncol, San Francisco, CA 94143 USA
[6] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Rheumatol, Los Angeles, CA 90095 USA
[7] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA
[8] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA
基金
美国国家卫生研究院;
关键词
MAGI-2/S-SCAM; glomerulosclerosis; D-ASPARTATE RECEPTORS; PDZ-DOMAIN; GLOMERULAR-DISEASE; NEPHROTIC SYNDROME; TUMOR-SUPPRESSOR; GUANYLATE KINASE; CELL POLARITY; MEMBRANE; NEPHRIN; PODOCYTES;
D O I
10.1073/pnas.1417297111
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-nullmice 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.
引用
收藏
页码:14876 / 14881
页数:6
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