Research on molecular mechanism of nephrotic syndrome

• Project/Area Number: 24591569
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: The University of Tokyo
• Principal Investigator: MIURA Kenichiro 東京大学, 医学部附属病院, 助教 (70408483)
• Co-Investigator(Kenkyū-buntansha): SEKINE Takashi 東邦大学, 医学部, 教授 (50255402) ; IGARASHI Takashi 独立行政法人国立成育医療研究センター, 総長 (70151256)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 小児腎・泌尿器学 / ネフローゼ症候群 / 腎臓疾患 / 遺伝学 / ネフローゼ / 蛋白尿 / 巣状糸球体硬化症 / MYH9

Outline of Final Research Achievements

It remains to be elucidated how idiopathic nephrotic syndrome including focal segmental glomerulosclerosis (FSGS) develops, while glomerular podocyte cytoskeletal proteins have recently emerged as candidate molecules associated with development of proteinuria. Mutations in the MYH9 gene, which encodes nonmuscle myosin heavy chain-IIA (NMMHC-IIA), cause Epstein syndrome and secondary FSGS in the kidney.
Firstly, we showed that NMMHC-IIA was localized at primary processes of the podocyte. Secondly, podocyte expression of NMMHC-IIA decreased specifically in Epstein syndrome and idiopathic nephrotic syndrome including primary FSGS. Thirdly, expression of other podocyte-associated proteins did not significantly changed in both FSGS and other chronic glomerulonephritis. These results suggest that NMMHC-IIA is strongly associated with development of idiopathic nephrotic syndrome, playing a pivotal role in maintenance of podocyte cytoskeleton.

Research Products

• [Journal Article] Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial (2014)
  • Author(s): Iijima K, Sako M, Nozu K, Mori R, Tuchida N, Kamei K, Miura K, Aya K, Nakanishi K, Ohtomo Y, Takahashi S, Tanaka R, Kaito H, Nakamura H, Ishikura K, Ito S, Ohashi Y.
  • Journal Title: Lancet Volume: 384 Issue: 9950 Pages: 1273-1281
  • DOI: 10.1016/s0140-6736(14)60541-9
  • Peer Reviewed
• [Journal Article] Decreased glomerular filtration as the primary factor of elevated circulating suPAR levels in focal segmental glomerulosclerosis. (2014)
  • Author(s): Harita Y, Ishizuka K, Tanego A, Sugawara N, Chikamoto H, Akioka Y, Tsurumi H, Miura K, Gotoh Y, Tsujita M, Yamamoto T, Horike K, Takeda A, Oka A, Igarashi T, Hattori M.
  • Journal Title: Pediatr Nephrol. Volume: 29 Issue: 9 Pages: 1553-1560
  • DOI: 10.1007/s00467-014-2808-5
  • Peer Reviewed
• [Journal Article] Epithelial protein lost in neoplasm modulates platelet-derived growth factor-mediated adhesion and motility of mesangial cells (2014)
  • Author(s): Haruko Tsurumi, et. al
  • Journal Title: Kidney International Volume: Epub Issue: 3 Pages: 548-557
  • DOI: 10.1038/ki.2014.85
  • Peer Reviewed / Open Access
• [Journal Article] LMX1B Mutation with Residual Transcriptional Activity as a Cause of Isolated Glomerulopathy. (2014)
  • Author(s): Isojima T, Harita Y, Furuyama M, Sugawara N, Ishizuka K, Horita S, Kajiho Y, Miura K, Igarashi T, Hattori M, Kitanaka S
  • Journal Title: Nephrol Dial Transplant Volume: 29 Issue: 1 Pages: 81-8
  • DOI: 10.1093/ndt/gft359
  • Peer Reviewed
• [Journal Article] Japanese Dent disease has a wider clinical spectrum than Dent disease in Europe/USA : genetic and clinical studies of 86 unrelated patients with low-molecular-weight proteinuria (2014)
  • Author(s): Sekine T, Komoda F, Miura K, Takita J, Shimadzu M, et al
  • Journal Title: Nephrol Dial Transplant Volume: 29 Issue: 2 Pages: 376-84
  • DOI: 10.1093/ndt/gft394
  • Peer Reviewed / Open Access
• [Journal Article] Podocyte expression of nonmuscle myosin heavy chain-IIA decreases in idiopathic nephrotic syndrome, especially in focal segmental glomerulosclerosis. (2013)
  • Author(s): Miura K, Kurihara H, Horita S, Chikamoto H, Hattori M, Harita Y, Tsurumi H, Kajiho Y, Sawada Y, Sasaki S, Igarashi T, Kunishima S, Sekine T.
  • Journal Title: Nephrol Dial Transplant. Volume: 28 Issue: 12 Pages: 2993-3003
  • DOI: 10.1093/ndt/gft350
  • Peer Reviewed
• [Journal Article] Mutational analyses of the ATP6V1B1 and ATP6V0A4 genes * in patients with primary distal renal tubular acidosis (2013)
  • Author(s): Miura K, Sekine T, Takahashi K, Takita J, Harita Y, et al
  • Journal Title: Nephrol Dial Transplant Volume: 28 Issue: 8 Pages: 2123-2130
  • DOI: 10.1093/ndt/gft216
  • Peer Reviewed
• [Journal Article] V2R mutations in partial nephrogenic diabetes insipidus highlight protean agonism of V2R antagonists (2012)
  • Author(s): Takahashi K, Makita N, et al.
  • Journal Title: J.Biol.Chem Volume: 287 Issue: 3 Pages: 2099-2106
  • DOI: 10.1074/jbc.m111.268797
  • Peer Reviewed
• [Journal Article] Early occurrence of nephrotic syndrome associated with cord blood stem cell transplantation (2012)
  • Author(s): Miura K, Sekine T, Takamizawa M, Terashima H, Furuya A, Koh K, Takita J, Ida K, Igarashi T
  • Journal Title: Clin Exp Nephrol Volume: 16 Issue: 1 Pages: 180-182
  • DOI: 10.1007/s10157-011-0538-6
  • NAID: 10030343374
  • Peer Reviewed
• [Journal Article] SIRPα interacts with nephrin at the podocyte slit diaphragm. (2012)
  • Author(s): Kajiho Y, Harita Y, Kurihara H, Horita S, Matsunaga A, Tsurumi H, Kanda S, Sugawara N, Miura K, Sekine T, Hattori S, Hattori M, Igarashi T.
  • Journal Title: FEBS J. Volume: 279 Issue: 17 Pages: 3010-3021
  • DOI: 10.1111/j.1742-4658.2012.08682.x
  • Peer Reviewed
• [Journal Article] Effect of dopamine on peripheral perfusion in very-low-birth-weight infants during the transitional period. (2012)
  • Author(s): Ishiguro A, Suzuki K, Sekine T, Kawasaki H, Itoh K, Kanai M, Ezaki S, Kunikata T, Sobajima H, Tamura M
  • Journal Title: Pediatr Res Volume: 72 Issue: 1 Pages: 86-89
  • DOI: 10.1038/pr.2012.37
  • Peer Reviewed
• [Journal Article] The long-term use of enalapril and hydrochlorothiazide in two novel mutations patients with Dent's disease type 1. (2012)
  • Author(s): Vaisbich MH, Henriques Ldos S, Igarashi T, Sekine T, Seki G, Koch VH.
  • Journal Title: J Bras Nefrol. Volume: 34 Pages: 78-81
  • Peer Reviewed
• [Presentation] Intermediate phenotypes of Dent-2 disease and Lowe syndrome in patients with OCRL mutations (2014)
  • Author(s): Miura K, Sekine T, Harita Y, Tsurumi H, Takahashi K, Takita J, Harita Y, Tajima A, Ishihara M, Hisano M, Hisano M, Nakakura H, Ashida A, Igarashi T
  • Organizer: American Society of Nephrology, Kidney Week 2014
  • Place of Presentation: フィラデルフィア（米国）
  • Year and Date: 2014-11-13
• [Presentation] 原発性尿細管性アシドーシスの全国疫学調査 (2014)
  • Author(s): 三浦健一郎，五十嵐隆，森貞直哉，飯島一誠
  • Organizer: 第57回日本腎臓学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-07-06
• [Presentation] 軽症Lowe症候群が疑われた2家系における遺伝子解析 (2014)
  • Author(s): 三浦健一郎、張田豊、鶴見晴子、吉田賢弘、貴田岡節子、関根孝司
  • Organizer: 第49回日本小児腎臓病学会学術集会
  • Place of Presentation: 秋田
  • Year and Date: 2014-06-07
• [Presentation] Detection of novel interstitial large deletions in the ATP6V0A4 gene and mutations in the ATP6V1B1 gene in patients with distal renal tubular acidosis. (2012)
  • Author(s): Miura K, Sekine T, Takahashi K, Takita J, Harita Y, Ishihara M, Hisano M, Igarashi T
  • Organizer: American Society of Nephrology Kidney Week 2012
  • Place of Presentation: San Diego, USA
• [Presentation] 先天性腎性尿崩症患者2例における新規Vasopressin２型受容体(V2R)遺伝子変異と機能解析
  • Author(s): 高木美奈子、三浦健一郎、沼倉周彦、藤野修平、鶴見晴子、磯島豪、早坂清、五十嵐隆、張田豊、北中幸子
  • Organizer: 第116回日本小児科学会
  • Place of Presentation: 広島国際会議場
• [Presentation] 小児ネフローゼ症候群患者における血中可溶性ウロキナーゼ受容体（suPAR）濃度の検討
  • Author(s): 張田豊、石塚喜世伸、三浦健一郎、鶴見晴子、種五淳史、菅原典子、秋岡祐子、服部元史、五十嵐隆
  • Organizer: 第56回日本腎臓学会
  • Place of Presentation: 東京国際フォーラム
• [Presentation] Mutational analyses of the ATP6V1B1 and ATP6V0A4 genes in patients with primary distal renal tubular acidosis
  • Author(s): Miura K, Sekine T, Takahashi K, Takita J, Harita Y, Tajima A, Ishihara M, Hisano M, Murai M, Igarashi T
  • Organizer: International Pediatric Nephrology Association 2013
  • Place of Presentation: Shanghai（中国）
• [Presentation] Osmotic demyelination syndrome～どうする？低Na血症の補正～
  • Author(s): 三浦健一郎
  • Organizer: Renal Weekend 2013―研修医のための輸液セミナー
  • Place of Presentation: 高槻市生涯学習センター（大阪）
  • Invited
• [Presentation] 常染色体劣性遠位尿細管性アシドーシスの臨床像と遺伝子変異の解析
  • Author(s): 三浦健一郎、張田豊、高橋和浩、滝田順子、五十嵐隆
  • Organizer: 第55回日本腎臓学会
  • Place of Presentation: 横浜
• [Presentation] 軽度の免疫異常とリンパ濾胞増殖症に膜性腎症を合併した1女児例
  • Author(s): 三浦健一郎、張田豊、高橋和浩、金森豊、宇於崎宏、五十嵐隆
  • Organizer: 第42回日本腎臓学会東部学術大会
  • Place of Presentation: 新潟
• [Presentation] 尿電解質の使い方
  • Author(s): 三浦健一郎
  • Organizer: 第47回日本小児腎臓病学会
  • Place of Presentation: 東京
  • Invited