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J Am Soc Nephrol. 2017 Sep;28(9):2654-2669. doi: 10.1681/ASN.2016121356. Epub 2017 May 24.

Glomerulosclerosis Induced by Deficiency of Membrane-Associated Guanylate Kinase Inverted 2 in Kidney Podocytes.

Author information

1
The Laboratory for Kidney Research (TMK project), Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
2
Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharmaceutical Corporation, Toda, Japan.
3
The Laboratory of Molecular Biology, Department of Molecular and Cell Biology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.
4
Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Juntendo University, Tokyo, Japan.
5
Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
6
Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York; and.
7
Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts.
8
The Laboratory for Kidney Research (TMK project), Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan; asanuma@tmk.med.kyoto-u.ac.jp.

Abstract

Membrane-associated guanylate kinase inverted 2 (MAGI-2) is a component of the slit diaphragm (SD) of glomerular podocytes. Here, we investigated the podocyte-specific function of MAGI-2 using newly generated podocyte-specific MAGI-2-knockout (MAGI-2-KO) mice. Compared with podocytes from wild-type mice, podocytes from MAGI-2-KO mice exhibited SD disruption, morphologic abnormalities of foot processes, and podocyte apoptosis leading to podocyte loss. These pathologic changes manifested as massive albuminuria by 8 weeks of age and glomerulosclerosis and significantly higher plasma creatinine levels at 12 weeks of age; all MAGI-2-KO mice died by 20 weeks of age. Loss of MAGI-2 in podocytes associated with decreased expression and nuclear translocation of dendrin, which is also a component of the SD complex. Dendrin translocates from the SD to the nucleus of injured podocytes, promoting apoptosis. Our coimmunoprecipitation and in vitro reconstitution studies showed that dendrin is phosphorylated by Fyn and dephosphorylated by PTP1B, and that Fyn-induced phosphorylation prevents Nedd4-2-mediated ubiquitination of dendrin. Under physiologic conditions in vivo, phosphorylated dendrin localized at the SDs; in the absence of MAGI-2, dephosphorylated dendrin accumulated in the nucleus. Furthermore, induction of experimental GN in rats led to the downregulation of MAGI-2 expression and the nuclear accumulation of dendrin in podocytes. In summary, MAGI-2 and Fyn protect dendrin from Nedd4-2-mediated ubiquitination and from nuclear translocation, thereby maintaining the physiologic homeostasis of podocytes, and the lack of MAGI-2 in podocytes results in FSGS.

KEYWORDS:

Dendrin; FSGS; MAGI-2; podocyte

PMID:
28539383
PMCID:
PMC5576941
DOI:
10.1681/ASN.2016121356
[Indexed for MEDLINE]
Free PMC Article

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