Molecular mechanisms of nephrotic syndrome induced by cytoskeletal protein abnormalities

2020 Fiscal Year Annual Research Report

• Project/Area Number: 18K07830
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: 三浦 健一郎 東京女子医科大学, 医学部, 准教授 (70408483)
• Co-Investigator(Kenkyū-buntansha): 安彦 行人 国立医薬品食品衛生研究所, 毒性部, 主任研究官 (40370944) [Withdrawn] ; 栗原 秀剛 藍野大学, 医療保健学部, 教授 (80311976)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ネフローゼ症候群 / 巣状分節性糸球体硬化症 / ポドサイト / MYH9 / Epstein症候群

Outline of Annual Research Achievements

難治性ネフローゼ症候群は高度蛋白尿、腎組織の巣状糸球体硬化症（FSGS）、末期腎不全
を来す疾患であり、その病態解明は小児腎疾患診療において最大課題の一つである。細胞骨格蛋白であるミオシン重鎖MYH9は糸球体上皮細胞（ポドサイト）に発現しており、その異常はEpstein症候群を起こし、腎組織はFSGSを呈する。また、遺伝子異常によらない特発性FSGSのポドサイトでも特異的にMYH9の発現が低下しており、MYH9は蛋白尿の濾過障壁として重要と考えられているポドサイト内で形態維持に重要な役割を果たしていることが考えられる。今回、MYH9の病的意義について解析するため、MYH9変異の時期特異的/組織特異的ノックインマウスを作製した。まず、MYH9-R702Cneoマウスでは、ヒトEpstein症候群と同様の血液学的異常、聴力低下、腎障害を起こすことが確認された。次に、MYH9-R702CneoマウスとNPHS2-CreERT2マウスを交配し、ダブルヘテロマウスすなわち腎特異的ノックインマウスを作製した。生後4週でタモキシフェンを投与したところ、生後13週で、蛋白尿の増加を確認した。
また、ヒトEpstein症候群7例の腎病理所見の解析を行い、メサンギウム増殖性腎炎4例、FSGS2例、IgA腎症1例を認めた。7例全例でメサンギウム増殖を認めた。蛍光抗体染色所見が得られた6例のうち、1例は免疫グロブリン・補体の沈着はなかったが、他の5例ではIgG, IgAなどの免疫グロブリンおよびC1q、C3の沈着を認め、5例全例に電顕でメサンギウム領域またはパラメサンギウム領域の高電子密度沈着物を認めた。病理画像の得られた2例では、糸球体係蹄の二重化、内皮下腔の拡大、メサンギウム融解など内皮障害の所見がみられた。

Research Products

• [Journal Article] Any modality of renal replacement therapy can be a treatment option for Joubert syndrome (2021)
  • Author(s): Takagi Yoko、Miura Kenichiro、Yabuuchi Tomoo、Kaneko Naoto、Ishizuka Kiyonobu、Takei Mariko、Yajima Chikage、Ikeuchi Yuka、Kobayashi Yasuko、Takizawa Takumi、Hisano Masataka、Tsurusaki Yoshinori、Matsumoto Naomichi、Hattori Motoshi
  • Journal Title: Scientific Reports Volume: 11 Pages: 462
  • DOI: 10.1038/s41598-020-80712-4
  • Peer Reviewed / Open Access
• [Journal Article] Valganciclovir prophylaxis for cytomegalovirus infection in pediatric kidney transplant recipients: a single-center experience (2021)
  • Author(s): Iida Takaya、Miura Kenichiro、Ban Hideki、Ando Taro、Shirai Yoko、Ishiwa Sho、Shiratori Atsutoshi、Kaneko Naoto、Yabuuchi Tomoo、Ishizuka Kiyonobu、Takaiwa Masanori、Suyama Kazuhide、Hisano Masataka、Hattori Motoshi
  • Journal Title: Clinical and Experimental Nephrology Volume: - Pages: -
  • DOI: 10.1007/s10157-021-02020-z
  • Peer Reviewed
• [Journal Article] Amount and selectivity of proteinuria may predict the treatment response in post-transplant recurrence of focal segmental glomerulosclerosis: a single-center retrospective study (2021)
  • Author(s): Ban Hideki、Miura Kenichiro、Kaneko Naoto、Shirai Yoko、Yabuuchi Tomoo、Ishizuka Kiyonobu、Chikamoto Hiroko、Akioka Yuko、Shimizu Satoru、Ishida Hideki、Tanabe Kazunari、Hattori Motoshi
  • Journal Title: Pediatric Nephrology Volume: - Pages: -
  • DOI: 10.1007/s00467-021-04951-x
  • Peer Reviewed
• [Journal Article] Chronic Active Antibody-Mediated Rejection with Linear IgG Deposition on Glomerular Capillaries in a Kidney Transplant Recipient (2020)
  • Author(s): Miura Kenichiro、Shirai Yoko、Kaneko Naoto、Yabuuchi Tomoo、Ishizuka Kiyonobu、Horita Shigeru、Furusawa Miyuki、Unagami Kohei、Okumi Masayoshi、Ishida Hideki、Tanabe Kazunari、Koike Junki、Honda Kazuho、Yamaguchi Yutaka、Hattori Motoshi
  • Journal Title: Nephron Volume: 144 Pages: 97～101
  • DOI: 10.1159/000511322
  • Peer Reviewed / Open Access
• [Journal Article] Individualized concept for the treatment of autosomal recessive polycystic kidney disease with end‐stage renal disease (2020)
  • Author(s): Miura Kenichiro、Sato Yasuyuki、Yabuuchi Tomoo、Kaneko Naoto、Ishizuka Kiyonobu、Chikamoto Hiroko、Akioka Yuko、Nawashiro Yuri、Hisano Masataka、Imamura Hideaki、Miyai Takayuki、Sakamoto Seisuke、Kasahara Mureo、Fuchinoue Shohei、Okumi Masayoshi、Ishida Hideki、Tanabe Kazunari、Hattori Motoshi
  • Journal Title: Pediatric Transplantation Volume: 24 Pages: e13690
  • DOI: 10.1111/petr.13690
  • Peer Reviewed
• [Journal Article] Nonosmotic secretion of arginine vasopressin and salt loss in hyponatremia in Kawasaki disease (2020)
  • Author(s): Miura Kenichiro、Harita Yutaka、Takahashi Naoto、Tsurumi Haruko、Yasudo Hiroki、Isojima Tsuyoshi、Takizawa Keiichi、Toyofuku Etsushi、Nishimoto Hajime、Takamizawa Masaru、Ando Taro、Sugawa Masahiro、Yanagisawa Atsuhiro、Inatomi Jun、Nogimori Yoshitsugu、Kinumaki Akiko、Namai Yoshiyuki、Hattori Motoshi、Oka Akira
  • Journal Title: Pediatrics International Volume: 62 Pages: 363～370
  • DOI: 10.1111/ped.14036
  • Peer Reviewed
• [Journal Article] Long‐term outcome of renal transplantation in childhood‐onset anti‐neutrophil cytoplasmic antibody?associated vasculitis (2020)
  • Author(s): Nagasawa Takeshi、Miura Kenichiro、Kaneko Naoto、Yabuuchi Tomoo、Ishizuka Kiyonobu、Chikamoto Hiroko、Akioka Yuko、Hisano Masataka、Hattori Motoshi
  • Journal Title: Pediatric Transplantation Volume: 24 Pages: e13656
  • DOI: 10.1111/petr.13656
  • Peer Reviewed
• [Journal Article] Validation of the Japanese Transition Readiness Assessment Questionnaire (2020)
  • Author(s): Sato Yuki、Ochiai Ryota、Ishizaki Yuko、Nishida Toshihiko、Miura Kenichiro、Taki Atsuko、Tani Yumi、Naito Mariko、Takahashi Yoshimitsu、Yaguchi‐Saito Akiko、Hattori Motoshi、Nakayama Takeo
  • Journal Title: Pediatrics International Volume: 62 Pages: 221～228
  • DOI: 10.1111/ped.14086
  • Peer Reviewed
• [Journal Article] Kidney function of Japanese children undergoing kidney transplant with preemptive therapy for cytomegalovirus infection (2020)
  • Author(s): Gotoh Yoshimitsu、Shishido Seiichiro、Hamasaki Yuko、Watarai Yoshihiko、Hattori Motoshi、Miura Kenichiro、Ishizuka Kiyonobu、Fujita Naoya、Saito Kazuhide、Nakagawa Yuki、Hotta Kiyohiko、Hataya Hiroshi、Hamada Riku、Sato Hiroyuki、Kitayama Hirotsugu、Ishikura Kenji、Honda Masataka、Uemura Osamu
  • Journal Title: Transplant Infectious Disease Volume: 22 Pages: e13271
  • DOI: 10.1111/tid.13271
  • Peer Reviewed
• [Journal Article] Incomplete cryptic splicing by an intronic mutation of OCRL in patients with partial phenotypes of Lowe syndrome (2020)
  • Author(s): Nakano Eiji、Yoshida Amine、Miyama Yudai、Yabuuchi Tomoo、Kajiho Yuko、Kanda Shoichiro、Miura Kenichiro、Oka Akira、Harita Yutaka
  • Journal Title: Journal of Human Genetics Volume: 65 Pages: 831～839
  • DOI: 10.1038/s10038-020-0773-3
  • Peer Reviewed
• [Journal Article] Clinical and genetic characterization of nephropathy in patients with nail-patella syndrome (2020)
  • Author(s): Harita Yutaka、Urae Seiya、Akashio Riki、Isojima Tsuyoshi、Miura Kenichiro、Yamada Takeshi、Yamamoto Katsusuke、Miyasaka Yasunori、Furuyama Masayuki、Takemura Tsukasa、Gotoh Yoshimitsu、Takizawa Hideki、Tamagaki Keiichi、Ozawa Atsushi、Ashida Akira、Hattori Motoshi、Oka Akira、Kitanaka Sachiko
  • Journal Title: European Journal of Human Genetics Volume: 28 Pages: 1414～1421
  • DOI: 10.1038/s41431-020-0655-3
  • Peer Reviewed
• [Journal Article] Renal hypoplasia can be the cause of membranous nephropathy-like lesions (2020)
  • Author(s): Takizawa Keiichi、Miura Kenichiro、Kaneko Naoto、Yabuuchi Tomoo、Ishizuka Kiyonobu、Kanda Shoichiro、Harita Yutaka、Akioka Yuko、Horita Shigeru、Taneda Sekiko、Honda Kazuho、Hattori Motoshi
  • Journal Title: Clinical and Experimental Nephrology Volume: 24 Pages: 813～820
  • DOI: 10.1007/s10157-020-01902-y
  • Peer Reviewed
• [Journal Article] Rapid progression to end-stage renal disease in a child with IgA-dominant infection-related glomerulonephritis associated with parvovirus B19 (2020)
  • Author(s): Shirai Yoko、Miura Kenichiro、Yabuuchi Tomoo、Nagasawa Takeshi、Ishizuka Kiyonobu、Takahashi Kazuhiro、Taneda Sekiko、Honda Kazuho、Yamaguchi Yutaka、Suzuki Hitoshi、Suzuki Yusuke、Hattori Motoshi
  • Journal Title: CEN Case Reports Volume: 9 Pages: 423～430
  • DOI: 10.1007/s13730-020-00501-w
  • Peer Reviewed
• [Journal Article] Pathological findings of initial-phase postrenal acute kidney injury (2020)
  • Author(s): Iida Takaya、Miura Kenichiro、Hattori Motoshi
  • Journal Title: Clinical and Experimental Nephrology Volume: 24 Pages: 974～975
  • DOI: 10.1007/s10157-020-01916-6
  • Peer Reviewed
• [Journal Article] Morphologic Analysis of Urinary Podocytes in Focal Segmental Glomerulosclerosis (2020)
  • Author(s): Shirai Yoko、Miura Kenichiro、Yokoyama Takashi、Horita Shigeru、Nakayama Hideki、Seino Hiroshi、Ando Taro、Shiratori Atsutoshi、Yabuuchi Tomoo、Kaneko Naoto、Ishiwa Sho、Ishizuka Kiyonobu、Hara Masanori、Hattori Motoshi
  • Journal Title: Kidney360 Volume: 2 Pages: 477～486
  • DOI: 10.34067/KID.0005612020
  • Peer Reviewed / Open Access
• [Journal Article] 巣状分節性糸球体硬化症 (2020)
  • Author(s): 三浦健一郎、金子直人、服部元史
  • Journal Title: 日本アフェレシス学会雑誌 Volume: 39 Pages: 132～138
• [Journal Article] 原疾患の再発―FSGS (2020)
  • Author(s): 三浦健一郎、服部元史
  • Journal Title: 腎と透析 Volume: 89 Pages: 992～996
• [Presentation] Response to steroid and immunosuppressive therapies may predict post-transplant recurrence of focal segmental glomerulosclerosis. (2021)
  • Author(s): Miura K, Ando T, Kanda S, Hashimoto T, Kaneko N, Ishizuka K, Hamada R, Hataya H, Hotta K, Gotoh Y, Nishiyama K, Hamasaki Y, Shishido S, Fujita N, Hattori M.
  • Organizer: 14th Asian Congress of Pediatric Nephrology
  • Int'l Joint Research
• [Presentation] Long-term renal prognosis of Lowe syndrome. (2020)
  • Author(s): Miura K, Yabuuchi T, Ishiwa S, Harita Y, Ishizuka K, Kanda S, Sato A, Isojima T, Hamada R, Ishikura K, Igarashi T, Hattori M.
  • Organizer: 18th Asian Pacific Congress of Nephrology
  • Int'l Joint Research
• [Presentation] 難治性ネフローゼ症候群 (2020)
  • Author(s): 三浦健一郎、服部元史
  • Organizer: 第41回日本アフェレシス学会学術大会