Elucidation of podocyte-specific TGF-beta suppression mechanism using R3hdml and examination of therapeutic application

• Project/Area Number: 16K19530
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: Chiba University
• Principal Investigator: Ishikawa Takahiro 千葉大学, 医学部附属病院, 特任助教 (00749426)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ポドサイト / 糖尿病性腎症 / TGF-β / p38MAPK / 糖尿病腎症

Outline of Final Research Achievements

The purpose of this study was to elucidate the role of podocyte-specific gene R3hdml in diabetic nephropathy.
In studies using cultured podocytes, R3hdml was found to suppress apoptosis of podocytes through suppression of p38 MAPK phosphorylation among MAPKs. In addition, changes in glomerular basement membrane and podocyte foot processes characteristic of diabetic nephropathy were observed in R3hdml knockout mice. In addition, albuminuria increased when diabetes was induced in R3hdml knockout mice. Furthermore, it was revealed that in R3hdml overexpressing mice, albumin excretion in urine is reduced in diabetic state as compared to wild type under the same condition. Thus, R3hdml may be a protective factor in the development of diabetic nephropathy.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、将来的なR3hdmlを用いたポドサイト特異的な糖尿病性腎症の治療法を確立に繋がる可能性がある。

Research Products

• [Journal Article] Physician-initiated clinical study of limb ulcers treated with a functional peptide, SR-0379: from discovery to a randomized, double-blind, placebo-controlled trial (2018)
  • Author(s): Nakagami H, Sugimoto K, Ishikawa T, Fujimoto T, Yamaoka T, Hayashi M, Kiyohara E, Ando H, Terabe Y, Takami Y, Yamamoto K, Takeya Y, Takemoto M, Koshizaka M, Ebihara T, Nakamura A, Nishikawa M, Yao XJ, Hanaoka H, Katayama I, Yokote K, Rakugi H
  • Journal Title: NPJ Aging Mech Dis Volume: 4 Issue: 1 Pages: 2-2
  • DOI: 10.1038/s41514-018-0021-7
  • Peer Reviewed / Open Access
• [Journal Article] Serum podocalyxin levels correlate with carotid intima media thickness, implicating its role as a novel biomarker for atherosclerosis (2018)
  • Author(s): Shoji Mayumi、Takemoto Minoru、Kobayashi Kazuki、Shoji Toshihiro、Mori Satoka、Sagara Jun-ichi、Kurosawa Hiroyuki、Hirayama Yoshiaki、Sakamoto Kenichi、Ishikawa Takahiro、Koshizaka Masaya、Maezawa Yoshiro、Yokote Koutaro
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 245-245
  • DOI: 10.1038/s41598-017-18647-6
  • Peer Reviewed / Open Access
• [Journal Article] Biallelic WRN Mutations in Newly Identified Japanese Werner Syndrome Patients (2018)
  • Author(s): Maezawa Y, Kato H, Takemoto M, Watanabe A, Koshizaka M, Ishikawa T, Sargolzaeiaval F, Kuzuya M, Wakabayashi H, Kusaka T, Yokote K, Oshima J
  • Journal Title: Mol Syndromol Volume: 9 Issue: 4 Pages: 214-218
  • DOI: 10.1159/000489055
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] N-3 polyunsaturated fatty acids improve lipoprotein particle size and concentration in Japanese patients with type 2 diabetes and hypertriglyceridemia:a pilot study (2018)
  • Author(s): Ide K, Koshizaka M, Tokuyama H, Tokuyama T, Ishikawa T, Maezawa Y, Takemoto M, Yokote K
  • Journal Title: Lipids Health Dis Volume: 17 Issue: 1 Pages: 51-51
  • DOI: 10.1186/s12944-018-0706-8
  • Peer Reviewed / Open Access
• [Journal Article] Werner syndrome: a model for sarcopenia due to accelerated aging (2017)
  • Author(s): Yamaga Masaya、Takemoto Minoru、Shoji Mayumi、Sakamoto Kenichi、Yamamoto Masashi、Ishikawa Takahiro、Koshizaka Masaya、Maezawa Yoshiro、Kobayashi Kazuki、Yokote Koutaro
  • Journal Title: Aging Volume: 9 Issue: 7 Pages: 1738-1744
  • DOI: 10.18632/aging.101265
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of ipragliflozin and metformin for visceral fat reduction in patients with type 2 diabetes receiving treatment with dipeptidyl peptidase-4 inhibitors in Japan: a study protocol for a prospective, multicentre, blinded-endpoint phase IV randomised controlled trial (PRIME-V study) (2017)
  • Author(s): Koshizaka Masaya、Ishikawa Ko、Ishikawa Takahiro、Kobayashi Kazuki、Takemoto Minoru、Horikoshi Takuro、Shimofusa Ryota、Takahashi Sho、Nagashima Kengo、Sato Yasunori、Tatsuno Ichiro、Terano Takashi、Hashimoto Naotake、Kuribayashi Nobuichi、Uchida Daigaku、Yokote Koutaro
  • Journal Title: BMJ Open Volume: 7 Issue: 5 Pages: e015766-e015766
  • DOI: 10.1136/bmjopen-2016-015766
  • Peer Reviewed / Open Access
• [Journal Article] Continuous glucose monitoring reveals hypoglycemia risk in elderly patients with type 2 diabetes mellitus. (2017)
  • Author(s): Ishikawa T, Koshizaka M, Maezawa Y, Takemoto M, Tokuyama Y, Saito T, Yokote K.
  • Journal Title: J Diebetes Invest Volume: - Issue: 1 Pages: 69-74
  • DOI: 10.1111/jdi.12676
  • Peer Reviewed / Open Access
• [Journal Article] Recent trends in WRN gene mutation patterns in individuals with Werner syndrome. (2017)
  • Author(s): Yamaga M, Takemoto M, Takada-Watanabe A, Koizumi N, Kitamoto T, Sakamoto K, Ishikawa T, Koshizaka M, Maezawa Y, Yokote K
  • Journal Title: J Am Geriatr Soc Volume: 印刷中 Issue: 8 Pages: 1853-1856
  • DOI: 10.1111/jgs.14906
  • Peer Reviewed / Open Access
• [Presentation] 新規TGF-βシグナル抑制因子であるR3hdmlのポドサイトにおける機能解析 (2016)
  • Author(s): 石川崇広、竹本稔、秋元義弘、楊國昌、坂本憲一、正司真弓、山賀政弥 、井出真太郎 、井出佳奈 、前澤善朗 、小林一貴、横手幸太郎
  • Organizer: 第59回 糖尿病学会年次学術集会
  • Place of Presentation: 国立京都国際会館(京都府京都市)
  • Year and Date: 2016-05-19