Podocyte-tubular epithelial cell interaction plays a role to prevent tubular injury

• Project/Area Number: 15H04836
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: University of Fukui
• Principal Investigator: Iwano Masayuki 福井大学, 学術研究院医学系部門, 教授 (20275324)
• Co-Investigator(Kenkyū-buntansha): 松阪 泰二 東海大学, 医学部, 教授 (50317749) ; 栗原 秀剛 藍野大学, 医療保健学部, 教授 (80311976)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: FSP1 / ポドサイト / 尿細管上皮細胞 / Nrf2 / 抗酸化作用 / 急性腎障害 / AKI / シスプラチン腎症 / HO-1 / チオレドキシン / SOD / RAGE / エクソソーム / ＦＳＰ１ / バイオマーカー / 糸球体腎炎 / 半月体 / 尿細管障害

Outline of Final Research Achievements

In human active glomerulonephritis, fibroblast specific protein 1 (FSP1) was highly expressed in podocytes. In this study, we investigated biological effects of FSP1 which can be excreted from podocytes in vitro and in vivo. Recombinant FSP1 (rFSP1) induced HO-1, SOD, and thioredoxin expression in tubular epithelial cells (TEC) via Nrf2 activation and rFSP1 exerted antioxidant effects and anti-apoptotic effects on TEC. rFSP1 could ameliorate acute tubular injury in cisplatin nephrotoxicity. In transgenic mice in which FSP1 was specifically expressed in podocytes, tubular injury in cisplatin nephrotoxicity was also ameliorated, which suggests podocyte-TEC interaction.

Academic Significance and Societal Importance of the Research Achievements

AKIは生命予後を著明に低下させる重要な病態である。しかし現在のところAKIに対する有効な予防薬および治療薬が存在しないため、世界中で精力的に研究が行われている。分泌型FSP1は、抗炎症作用、抗アポトーシス作用および抗酸化作用を併せ持つことから、AKI新規治療薬として有望である。増加の一途を辿る透析患者数に歯止めをかけるために、腎臓病領域における新薬開発は喫緊の課題である。本研究は、創薬に直結する意義深いものである。

Research Products

• [Journal Article] Elevated Levels of Urinary Extracellular Vesicle Fibroblast-Specific Protein 1 in Patients with Active Crescentic Glomerulonephritis. (2019)
  • Author(s): Morikawa Y, Takahashi N, Kamiyama K, Nishimori K, Nishikawa Y, Morita S, Kobayashi M, Fukushima S, Yokoi S, Mikami D, Kimura H, Kasuno K, Yashiki T, Naiki H, Hara M, Iwano M.
  • Journal Title: Nephron Volume: 141 Issue: 3 Pages: 177-187
  • DOI: 10.1159/000495217
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The age-related changes of dietary phosphate responsiveness in plasma 1,25-dihydroxyvitamin D levels and renal Cyp27b1 and Cyp24a1 gene expression is associated with renal α-Klotho gene expression in mice (2018)
  • Author(s): Yoshikawa R, Yamamoto H, Nakahashi O, Kagawa T, Tajiri M, Nakao M, Fukuda S, Arai H, Masuda M, Iwano M, Takeda E, Taketani Y.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 62 Issue: 1 Pages: 68-74
  • DOI: 10.3164/jcbn.17-20
  • NAID: 130006301221
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Journal Article] Tubulointerstitial Nephritis with IgM-Positive Plasma Cells. (2017)
  • Author(s): Takahashi N, Kimura H et al
  • Journal Title: J Am Soc Nephrol. Volume: 28 Issue: 12 Pages: 3688-3698
  • DOI: 10.1681/asn.2016101074
  • Peer Reviewed / Open Access
• [Journal Article] Short-chain fatty acids, GPR41 and GPR43 ligands, inhibit TNF-α-induced MCP-1 expression by modulating p38 and JNK signaling pathways in human renal cortical epithelial cells. (2017)
  • Author(s): Kobayashi M, Mikami D, Kimura H, Kamiyama K, Morikawa Y, Yokoi S, Kasuno K, Takahashi N, Taniguchi T, Iwano M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 486 Issue: 2 Pages: 499-505
  • DOI: 10.1016/j.bbrc.2017.03.071
  • Peer Reviewed
• [Journal Article] Mizoribine therapy combined with steroids and mizoribine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome. (2017)
  • Author(s): Saito T, Iwano M, Matsumoto K, Mitarai T, Yokoyama H, Yorioka N, Nishi S, Yoshimura A, Sato H, Ogahara S, Sasatomi Y, Kataoka Y, Ueda S, Koyama A, Maruyama S, Nangaku M, Imai E, Matsuo S, Tomino Y; Refractory Nephrotic Syndrome Study Group.
  • Journal Title: Clin Exp Nephrol. Volume: 21 Issue: 6 Pages: 961-970
  • DOI: 10.1007/s10157-016-1340-2
  • NAID: 120006373812
• [Journal Article] Mizoribine therapy combined with steroids and mizoribine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome. (2017)
  • Author(s): Saito T, Iwano M, Matsumoto K, Mitarai T, Yokoyama H, Yorioka N, Nishi S, Yoshimura A, Sato H, Ogahara S, Sasatomi Y, Kataoka Y, Ueda S, Koyama A, Maruyama S, Nangaku M, Imai E, Matsuo S, Tomino Y
  • Journal Title: Clin Exp Nephrol Volume: 印刷中
  • NAID: 120006373812
  • Peer Reviewed
• [Journal Article] Serum CETP status is independently associated with reduction rates in LDL-C in pitavastatin-treated diabetic patients and possible involvement of LXR in its association. (2016)
  • Author(s): Shimada A, Kimura H, (14人中2番目)
  • Journal Title: Lipids in Health and Disease Volume: 15 Issue: 1 Pages: 57-68
  • DOI: 10.1186/s12944-016-0223-6
  • NAID: 120005756530
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Renal resistive index correlates with peritubular capillary loss and arteriosclerosis in biopsy tissues from patients with chronic kidney disease. (2015)
  • Author(s): Kimura N, Kimura H, (10人中2番目)
  • Journal Title: Clin Exp Nephrol Volume: 19 Issue: 6 Pages: 1114-1119
  • DOI: 10.1007/s10157-015-1116-0
  • Peer Reviewed
• [Presentation] シスプラチン腎症改善効果より示唆された分泌型FSP1を介したポドサイトー尿細管上皮細胞連関 (2018)
  • Author(s): 横井靖二、西森一久、森田紗由、小林麻美子、西川雄大、森川幸恵、福島佐知子、三上大輔、高橋直生、糟野健司、木村秀樹、岩野正之
  • Organizer: 日本腎臓学会学術総会
• [Presentation] Intracellular Thioredoxin Depletion Triggers Tubular Epithelial G2/M arrest in Acute Kidney Injury (2018)
  • Author(s): Kenji Kasuno, Seiji Yokoi, Naoki Takahashi, Daisuke Mikami, Kazuhisa Nishimori, Sachiko Fukushima, Yukie Morikawa, Mamiko Kobayashi, Sayu Morita, Hideki Kimura, Masayuki Iwano
  • Organizer: 日本腎臓学会学術総会
• [Presentation] Elevated Levels of Urinary Extracellular Vesicle Fibroblast-Specific Protein 1 in Patients with Active Crescentic Glomerulonephritis (2018)
  • Author(s): Morikawa Y, Takahashi N, Kamiyama K, Nishimori K, Nishikawa Y, Morita S, Kobayashi M, Fukushima S, Yokoi S, Mikami D, Kimura H, Kasuno K, Iwano M.
  • Organizer: Kidney Week 2018
  • Int'l Joint Research
• [Presentation] ネフローゼ症候群の発症機序（オーバーヴュー） (2017)
  • Author(s): 岩野正之
  • Organizer: 第47回日本腎臓学会西部学術大会
• [Presentation] 尿中エクソソーム内FSP1発現量は、活動性半月体形成性腎炎で増加する (2017)
  • Author(s): 森川幸恵、高橋直生、森田紗由、西川雄大、小林麻美子、福島佐知子、横井靖二、三上大輔、糟野健司、木村秀樹、岩野正之
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] ポドサイトにおけるFSP1(S100A4)発現の意義 (2016)
  • Author(s): 岩野正之、横井二
  • Organizer: 第46回日本腎臓学会西部学術大会
  • Place of Presentation: シーガイアコンベンションセンター（宮崎県宮崎市）
  • Year and Date: 2016-10-14
• [Presentation] ポドサイトにおけるFSP1(S100A4)発現の意義 (2016)
  • Author(s): 岩野正之
  • Organizer: 第46回日本腎臓学会西部学術大会
  • Place of Presentation: 宮崎
  • Year and Date: 2016-10-14
• [Patent(Industrial Property Rights)] 透析装置、制御装置、制御プログラム、および記録媒体 (2017)
  • Inventor(s): 西森一久、糟野健司、岩野正之
  • Industrial Property Rights Holder: 西森一久、糟野健司、岩野正之
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-195294
  • Filing Date: 2017
• [Patent(Industrial Property Rights)] 尿中の急性腎障害マーカーのＣＬＥＩＡ法による迅速測定方法 (2017)
  • Inventor(s): 糟野健司、横井靖二、岩野正之
  • Industrial Property Rights Holder: 糟野健司、横井靖二、岩野正之
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-082836
  • Filing Date: 2017
• [Patent(Industrial Property Rights)] 抗酸化剤および腎障害処置剤 (2017)
  • Inventor(s): 岩野正之、木村秀樹、横井靖二
  • Industrial Property Rights Holder: 岩野正之、木村秀樹、横井靖二
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-055092
  • Filing Date: 2017-03-21