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

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.

• Authors: Naritoshi Shirata, Kan-Ichiro Ihara, Kanae Yamamoto-Nonaka, Takuto Seki, Shin-Ichi Makino, Juan Alejandro Oliva Trejo, Takafumi Miyake, Hiroyuki Yamada, Kirk Nicholas Campbell, Takahiko Nakagawa, Kiyoshi Mori, Motoko Yanagita, Peter Mundel, Katsuhiko Nishimori, Katsuhiko Asanuma
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 28 Issue 9 Pg. 2654-2669 (Sep 2017) ISSN: 1533-3450 [Electronic] United States
• PMID: 28539383 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 by the American Society of Nephrology.

Chemical References

• Adaptor Proteins, Signal Transducing
• Endosomal Sorting Complexes Required for Transport
• Fyb protein, mouse
• Nerve Tissue Proteins
• dendrin
• Creatinine
• NEDD4L protein, rat
• Nedd4 Ubiquitin Protein Ligases
• Nedd4 protein, rat
• Nedd4l protein, mouse
• Ubiquitin-Protein Ligases
• Guanylate Kinases
• Magi2 protein, mouse
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Ptpn1 protein, mouse

Topics

• Active Transport, Cell Nucleus (genetics)
• Adaptor Proteins, Signal Transducing (deficiency, genetics, metabolism)
• Albuminuria (genetics, urine)
• Animals
• Apoptosis (genetics)
• Creatinine (blood)
• Down-Regulation
• Endosomal Sorting Complexes Required for Transport (metabolism)
• Female
• Glomerulosclerosis, Focal Segmental (genetics, metabolism)
• Guanylate Kinases (deficiency, genetics, metabolism)
• Male
• Mice
• Mice, Knockout
• Nedd4 Ubiquitin Protein Ligases
• Nerve Tissue Proteins (metabolism)
• Phosphorylation
• Podocytes (pathology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (metabolism)
• Rats
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination