Activating hypoxia response for improving functions of renal EPO producing cells.

• Project/Area Number: 26860623
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Tohoku University
• Principal Investigator: Souma Tomokazu 東北大学, 医学系研究科, 非常勤講師 (20722531)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 腎性貧血 / 低酸素応答 / 腎エリスロポエチン産生細胞 / 貧血 / 線維化 / 低酸素

Outline of Final Research Achievements

This research project aimed to understand how renal erythropoietin-producing cells (REPCs) lose their physiological function and gain pathological characteristics under kidney injury. We used multiple mouse models and elucidated that the hypoxia signaling cascade is attenuated in inflammatory milieu in injured kidneys. We further found that activating hypoxia signaling by means of inhibiting HIF proryl hydroxylase, a master negative regulatory system of hypoxia responses, restored REPCs physiological function in hypoxic injured kidneys. Our research provides an explanation how PHD inhibitors, which are clinical trial for renal anemia, might work in injured kidneys in CKD patients.

Research Products

• [Int'l Joint Research] University of Connecticut Health Centre(米国)
• [Int'l Joint Research] Northwestern University(米国)
• [Journal Article] A Novel Method for Anti-HLA Antibody Detection Using Personalized Peptide Arrays. (2016)
  • Author(s): Liu P, Souma T, Wei AZ, Xie X, Luo X, Jin J.
  • Journal Title: Transplant Direct. Volume: 2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Erythropoietin Synthesis in Renal Myofibroblasts Is Restored by Activation of Hypoxia Signaling (2016)
  • Author(s): Tomokazu Souma, Masahiro Nezu, Daisuke Nakano, Shun Yamazaki, Ikuo Hirano, Hiroki Sekine, Takashi Dan, Kotaro Takeda, Guo-Hua Fong, Akira Nishiyama, Sadayoshi Ito, Toshio Miyata, Masayuki Yamamoto, Norio Suzuki
  • Journal Title: Journal of the american society of nephlorogy Volume: 27 Issue: 2 Pages: 428-438
  • DOI: 10.1681/asn.2014121184
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. (2016)
  • Author(s): Souma T, Tompson SW, Thomson BR, Siggs OM, Kizhatil K, John S, Wiggs JL, Pasutto F, Craig JE, Jin J, Quaggin SE, Young TL.
  • Journal Title: J Clin Invest. Volume: 126 Issue: 7 Pages: 2575-2575
  • DOI: 10.1172/jci85830
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nrf2 DEFICIENCY ALLEVIATES PERINATAL COMPLICATIONS IN PREGNANCY-ASSOCIATED HYPERTENSION MICE VIA ENHANCING PLACENTAL ANGIOGENESIS. (2016)
  • Author(s): Nezu M, Souma T, Yu L, Sekine H, Moriguchi T, Takahashi N, Ito S, Suzuki N, Yamamoto M.
  • Journal Title: J Hypertens Volume: 34
  • Peer Reviewed
• [Journal Article] Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression (2016)
  • Author(s): Nezu M, Souma T, Yu L, Suzuki T, Saigusa D, Ito S, Suzuki N, Yamamoto M.
  • Journal Title: Kidney Int Volume: 91 Issue: 2 Pages: 387-401
  • DOI: 10.1016/j.kint.2016.08.023
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 腎線維化と腎性貧血 (2015)
  • Author(s): 相馬友和、鈴木教郎
  • Journal Title: 日本腎臓学会雑誌 Volume: 57 Pages: 1193-1199
• [Journal Article] Renal erythropoietin-producing cells in health and disease. (2015)
  • Author(s): Souma T, Suzuki N, Yamamoto M
  • Journal Title: Front Physiol. Volume: 3 Pages: 167-167
  • DOI: 10.3389/fphys.2015.00167
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes. (2015)
  • Author(s): Tojo Y, Sekine H, Hirano I, Pan X, Souma T, Tsujita T, Kawaguchi S, Takeda N, Takeda K, Fong GH, Dan T, Ichinose M, Miyata T, Yamamoto M, Suzuki N.
  • Journal Title: Mol Cell Biol. Volume: 35 Issue: 15 Pages: 2658-2672
  • DOI: 10.1128/mcb.00161-15
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Indoxyl sulfate down-regulates SLCO4C1 transporter through up-regulation of GATA3 (2014)
  • Author(s): Yu L, Moriguchi T, Souma T, Takai J, Satoh H, Morito N, Engel JD, Yamamoto M
  • Journal Title: Molecular and Cellular Biology Volume: 8 Issue: 11 Pages: 1929-1941
  • DOI: 10.1128/mcb.01659-13
  • Peer Reviewed / Open Access
• [Journal Article] 腎エリスロポエチン産生細胞と腎臓病 (2014)
  • Author(s): 袮津昌宏、相馬友和、山本雅之
  • Journal Title: 日本臨牀 Volume: 72 Pages: 1691-1700
• [Presentation] アンジオポエチン受容体TEKの機能欠失変異は発達緑内障の原因である。 (2016)
  • Author(s): 相馬友和、Stuart Topmson、Benjamin Thomson、Terri Youna、Susan Quaggin
  • Organizer: 日本生化学会
  • Place of Presentation: 仙台市（仙台国際センター）
  • Int'l Joint Research
• [Presentation] Nrf2 activation in tubular cells prevents progression of AKI to CKD. (2015)
  • Author(s): Nezu M, Souma T, Ito S, Suzuki N, Yamamoto M
  • Organizer: ASN Kidney week 2015
  • Place of Presentation: San Diego, California
  • Year and Date: 2015-11-03
  • Int'l Joint Research
• [Presentation] Genetic Activation of Hypoxia-Signaling Restores Erythropoietin Synthesis in Renal Myofibroblasts (2014)
  • Author(s): Souma T, Nezu M, Ito S, Suzuki N, and Yamamoto M.
  • Organizer: ASN Kidney Week 2014
  • Place of Presentation: Philadelphia, Pennsylvania
  • Year and Date: 2014-11-13 – 2014-11-16
• [Presentation] Exploring the Nexus of Angiopoietin-Tie2 Signaling by Mass-Spectrometry for Establishing Therapeutic Strategies for Diabetic Nephropathy (2014)
  • Author(s): Souma T, Jin J, and Quaggin S
  • Organizer: ASN Kidney Week 2014
  • Place of Presentation: Philadelphia, Pennsylvania
  • Year and Date: 2014-11-13 – 2014-11-16