The role of MAGI-2 in maintenance of slit-diaphragm

• Project/Area Number: 18H02823
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Chiba University
• Principal Investigator: ASANUMA KATSUHIKO 千葉大学, 大学院医学研究院, 教授 (60449064)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2018: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 慢性腎臓病 / 蛋白尿 / ポドサイト / スリット膜 / MAI-2 / MAGI-2 / Dendrin / 腎臓

Outline of Final Research Achievements

We focused on the role of Membrane-associated guanylate kinase inverted 2 (MAGI-2) to investigate the mechanisms that orchestrate the localization of SD associated proteins. We found that MAGI-2 downregulation coincides with a reduced expression of SD associated proteins in a human kidney , and that a podocyte-specific deficiency of MAGI-2 in mice derogates the localization of Nephrin and Neph1. Although a deficiency of zonula occuldens-1 (ZO-1) downregulated the endogenous Neph1 expression, MAGI-2 recovered the Neph1 expression at the cellular edge in cultured mouse podocytes. Futhermore, overexpression of MAGI-2 preserved Nephrin localization on cell-cell contacts. Thus, the localization of Nephrin and Neph1 in intercellular junctions is regulated mainly via the PDZ domains of MAGI-2 together with other scaffold proteins. In summary, MAGI-2 stabilizes the localization of SD backbone proteins via its PDZ domain.

Academic Significance and Societal Importance of the Research Achievements

今回の研究で、血清蛋白の最終濾過障壁であるスリット膜の維持にMAGI-2が重要な働きを果たしていることがわかった。また、ヒト腎疾患でMAGI-2の発現が低下していることから、MAGI-2の発現を制御することが、慢性腎臓病に対する新いターゲットになることが判明した。

Research Products

• [Journal Article] Impairment of Proteasome Function in Podocytes Leads to CKD (2021)
  • Author(s): Makino Shin-ichi、Shirata Naritoshi、Oliva Trejo Juan Alejandro、Yamamoto-Nonaka Kanae、Yamada Hiroyuki、Miyake Takafumi、Mori Kiyoshi、Nakagawa Takahiko、Tashiro Yoshitaka、Yamashita Hirofumi、Yanagita Motoko、Takahashi Ryosuke、Asanuma Katsuhiko
  • Journal Title: Journal of the American Society of Nephrology Volume: 32 Issue: 3 Pages: 597-613
  • DOI: 10.1681/asn.2019101025
  • Peer Reviewed
• [Journal Article] MAGI-2 orchestrates the localization of backbone proteins in the slit diaphragm of podocytes (2021)
  • Author(s): Yamada Hiroyuki, Mukoyama Masashi, Asanuma Katsuhiko, et al.
  • Journal Title: Kidney International Volume: 99 Issue: 2 Pages: 382-395
  • DOI: 10.1016/j.kint.2020.09.027
  • Peer Reviewed / Open Access
• [Journal Article] Dynamin 1 is important for microtubule organisation and stabilisation in glomerular podocytes (2020)
  • Author(s): The Mon La , Tachibana, H., Li, S.A., Abe, T., Seiriki, S., Nagaoka, H., Takashima, E., Takeda, T., Ogawa, D., Makino, S., Asanuma, K., Watanabe, M., Tian, X., Ishibe, S., Sakane, A., Sasaki, T., Wada, J., Takei, K., Yamada, H.
  • Journal Title: FASEB Journal Volume: 34 Issue: 12 Pages: 16449-16463
  • DOI: 10.1096/fj.202001240rr
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Proteolytic cleavage of Podocin by Matriptase exacerbates podocyte injury (2020)
  • Author(s): Ozawa Shota、Matsubayashi Masaya、Nanaura Hitoki、Yanagita Motoko、Mori Kiyoshi、Asanuma Katsuhiko、Kajiwara Nobuyuki、Hayashi Kazuyuki、Ohashi Hiroshi、Kasahara Masato、Yokoi Hideki、Kataoka Hiroaki、Mori Eiichiro、Nakagawa Takahiko
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 47 Pages: 16002-16012
  • DOI: 10.1074/jbc.ra120.013721
  • Peer Reviewed / Open Access
• [Journal Article] A rare case of nephrotic syndrome associated with Dent’s disease: a case report (2020)
  • Author(s): Makino Shinichi、Empitu Maulana A.、Naito Toshimasa、Ishii Masayoshi、Wakabayashi Hanae、Lee Chiwei、Aizawa Masashi、Asanuma Katsuhiko
  • Journal Title: CEN Case Reports Volume: 9 Issue: 4 Pages: 380-384
  • DOI: 10.1007/s13730-020-00491-9
  • Peer Reviewed
• [Journal Article] Pivotal role of podocyte autophagy against glomerular endothelial dysfunction in diabetes. (2020)
  • Author(s): Yoshibayashi M, Kume S, Yasuda-Yamahara M, Yamahara K, Takeda N, Osawa N, Chin-Kanasaki M, Nakae Y, Yokoi H, Mukoyama M, Asanuma K, Maegawa H, Araki SI.
  • Journal Title: Biochem Biophys Res Commun. Volume: 525 Issue: 2 Pages: 319-325
  • DOI: 10.1016/j.bbrc.2020.02.088
  • Peer Reviewed / Open Access
• [Journal Article] Contribution of Coiled-Coil Assembly to Ca2+/Calmodulin-Dependent Inactivation of TRPC6 Channel and its Impacts on FSGS-Associated Phenotypes (2019)
  • Author(s): Polat Onur K.、Uno Masatoshi、Maruyama Terukazu、Tran Ha Nam、Imamura Kayo、Wong Chee Fah、Sakaguchi Reiko、Ariyoshi Mariko、Itsuki Kyohei、Ichikawa Jun、Morii Takashi、Shirakawa Masahiro、Inoue Ryuji、Asanuma Katsuhiko、Reiser Jochen、Tochio Hidehito、Mori Yasuo、Mori Masayuki X.
  • Journal Title: Journal of the American Society of Nephrology Volume: 30 Issue: 9 Pages: 1587-1603
  • DOI: 10.1681/asn.2018070756
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular assay for an intronic variant in NUP93 that causes steroid resistant nephrotic syndrome (2019)
  • Author(s): Rossanti Rini、Shono Akemi、Miura Kenichiro、Hattori Motoshi、Yamamura Tomohiko、Nakanishi Keita、Minamikawa Shogo、Fujimura Junya、Horinouchi Tomoko、Nagano China、Sakakibara Nana、Kaito Hiroshi、Nagase Hiroaki、Morisada Naoya、Asanuma Katsuhiko、Matsuo Masafumi、Nozu Kandai、Iijima Kazumoto
  • Journal Title: Journal of Human Genetics Volume: 64 Issue: 7 Pages: 673-679
  • DOI: 10.1038/s10038-019-0606-4
  • NAID: 120006653286
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neurofilament heavy polypeptide protects against reduction in synaptopodin expression and prevents podocyte detachment (2018)
  • Author(s): Wang Juan、Hidaka Teruo、Sasaki Yu、Tanaka Eriko、Takagi Miyuki、Shibata Terumi、Kubo Ayano、Trejo Juan Alejandro Oliva、Wang Lining、Asanuma Katsuhiko、Tomino Yasuhiko
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 17157-17171
  • DOI: 10.1038/s41598-018-35465-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MAGI-2 and scaffold proteins in glomerulopathy (2018)
  • Author(s): Empitu Maulana A.、Kadariswantiningsih Ika N.、Aizawa Masashi、Asanuma Katsuhiko
  • Journal Title: American Journal of Physiology-Renal Physiology Volume: 315 Issue: 5 Pages: F1336-F1344
  • DOI: 10.1152/ajprenal.00292.2018
  • Peer Reviewed
• [Journal Article] Expression of Cathepsin L and Its Intrinsic Inhibitors in Glomeruli of Rats With Puromycin Aminonucleoside Nephrosis (2018)
  • Author(s): Kubo Ayano、Shirato Isao、Hidaka Teruo、Takagi Miyuki、Sasaki Yu、Asanuma Katsuhiko、Ishidoh Kazumi、Suzuki Yusuke
  • Journal Title: Journal of Histochemistry & Cytochemistry Volume: 66 Issue: 12 Pages: 863-877
  • DOI: 10.1369/0022155418791822
  • Peer Reviewed
• [Journal Article] Rac1 in podocytes promotes glomerular repair and limits the formation of sclerosis (2018)
  • Author(s): Asao Rin、Seki Takuto、Takagi Miyuki、Yamada Hiroyuki、Kodama Fumiko、Hosoe-Nagai Yoshiko、Tanaka Eriko、Trejo Juan Alejandro Oliva、Yamamoto-Nonaka Kanae、Sasaki Yu、Hidaka Teruo、Ueno Takashi、Yanagita Motoko、Suzuki Yusuke、Tomino Yasuhiko、Asanuma Katsuhiko
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 5061-5061
  • DOI: 10.1038/s41598-018-23278-6
  • NAID: 120006517798
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RAGE-aptamer Blocks the Development and Progression of Experimental Diabetic Nephropathy. (2017)
  • Author(s): Matsui, T., Higashimoto, Y., Nishino, Y., Nakamura, N., Fukami, K., Yamagishi, S.
  • Journal Title: Diabetes Volume: 66 Issue: 1 Pages: 1683-1695
  • DOI: 10.1038/s41598-018-21176-5
  • NAID: 40021434304
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Membrane-ass0ciated guanylate kinase inverted 2は、ポドサイトのスリット膜の構造維持に必須である (2020)
  • Author(s): 山田博之、牧野慎市、柳田素子、淺沼克彦
  • Organizer: 第63回日本腎臓学会
• [Presentation] Membrane-associated guanylate kinase inverted 2 coordinates the localization of slit-diaphragm, backbone. (2020)
  • Author(s): Hiroyuki Yamada, Shinichi Makino, Motoko Yanagita, Katsuhiko Asanuma
  • Organizer: 18th Asian Pacific Congress of Nephrology
  • Int'l Joint Research
• [Presentation] A rare case of nephrotic syndrome associated with Dent disease. (2020)
  • Author(s): Shinichi Makino, Maulana A Empitu, Masayoshi Ishii, Masashi Aizawa, Katsuhiko Asanuma.
  • Organizer: ASN Kidney week 2020
  • Int'l Joint Research
• [Presentation] A case of AKI with nephrotic syndrome after intraperitoneal infection with methicillin-sensitive staphylococcus aureus (MSSA). (2020)
  • Author(s): Issei Okunaga, Shinichi Makino, Masashi Aizawa, Katsuhiko Asanuma.
  • Organizer: ASN Kidney week 2020
  • Int'l Joint Research
• [Presentation] OASIS in podocytes promoted tubular injury by suppressing PRKCI expression. (2020)
  • Author(s): Yoshiaki Miyake, Masanori Obana, Ayaha Yamamoto, Takeo Harada, Shunsuke Noda, Sayuri Mitsuoka, Koki Tanaka, Shota Tanaka, Kazunori Imaizumi, Katsuhiko Asanuma, Yasushi Fujio.
  • Organizer: ASN Kidney week 2020
  • Int'l Joint Research
• [Presentation] Analysis of relationship between proteasome and autophagy in podocytes using podocyte-specific proteasome impairment mice. (2020)
  • Author(s): Shinichi Makino, Hiroyuki Yamada, Ika N Kadariswantiningsih, Maulana A Empitu, Motoko Yanagita, Katsuhiko Asanuma.
  • Organizer: ASN Kidney week 2020
  • Int'l Joint Research
• [Presentation] 糸球体足細胞（ポドサイト）と糸球体基底膜の濾過障壁としての役割 (2019)
  • Author(s): 淺沼克彦
  • Organizer: 第５１回日本結合織学会学術大会
  • Invited
• [Presentation] ３次元診断による硬化糸球体の診断への試み (2019)
  • Author(s): 山田博之、淺沼克彦
  • Organizer: 第５１回日本結合織学会学術大会
  • Invited
• [Presentation] 蛋白尿の発症機序：GBM、ポドサイト (2019)
  • Author(s): 淺沼克彦
  • Organizer: 第62回日本腎臓学会学術総会
  • Invited
• [Presentation] Membrane-associated guanylate kinase inverted 2 coordinates slit-diaphragm proteins in podocytes (2019)
  • Author(s): Hiroyuki Yamada, Shinichi Makino, Takafumi Miyake, Hideki Yokoi, Katsuhiko Nishimori, Motoko Yanagita, Katsuhiko Asanuma
  • Organizer: The 62nd Annual Meeting of the Japanese Society of Nephrology
• [Presentation] The role of ubiquitin-proteasome system in podocytes (2018)
  • Author(s): Shinichi Makino、Naritoshi Shirata、Juan Alejandro Oliva Trejo、Kanae Yamamoto-Nonaka、Motoko Yanagita、Katsuhiko Asanuma.
  • Organizer: ISN FRONTIER
  • Int'l Joint Research
• [Presentation] Advanced optical clearing protocols could enable fine analysis of glomerulus three-dimensionally with confocal microscopy (2018)
  • Author(s): Hiroyuki Yamada, Shinichi Makino, Miyake Takafumi, Motoko Yanagita, Katsuhiko Asanuma.
  • Organizer: ASN Kidney Week,
  • Int'l Joint Research
• [Presentation] Optical clearing methods could visualize fine structure of podocyte and glomerulus three-dimensionally (2018)
  • Author(s): Hiroyuki Yamada, Shinichi Makino, Takafumi Miyake, Motoko Yanagida, Katsuhiko Asanuma.
  • Organizer: 第61回日本腎臓学会
• [Presentation] Dysfunction of proteasome in podocytes results in chronic kidney disease. (2018)
  • Author(s): Shinichi Makino,Juan Alejandro Oliva Trejo,Kanae Yamamoto-Nonaka,Motoko Yanagida Katsuhiko Asanuma.
  • Organizer: 第61回日本腎臓学会
• [Book] 腎と透析 (2020)
  • Author(s): 山田博之、淺沼克彦.
  • Total Pages: 5
  • Publisher: 東京医学社
• [Book] ３. 上皮細胞障害、IgA腎症の病態と治療 (2019)
  • Author(s): 山田博之、淺沼克彦
  • Publisher: 中外医学社