Innovative drug development of the diabetic nephropathy which targeted mineralocorticoid receptor's co-repressor

• Project/Area Number: 16K09600
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Tohoku University
• Principal Investigator: Kudo Masataka 東北大学, 大学病院, 准教授 (20509583)
• Co-Investigator(Kenkyū-buntansha): 菅原 明 東北大学, 医学系研究科, 教授 (90270834)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 創薬 / 糖尿病性腎症 / アルドステロン / 内科 / 糖尿病 / 循環器・高血圧 / 薬理学

Outline of Final Research Achievements

Using a type 1 diabetic nephropathy model (iNOS/RAGE double TG mouse), we aimed to develope a new drug which regulate the expression of mineral corticoid receptor's co-repressor and test the depression effect of diabetic nephropathy and a utility of the combination with the existing MR antagonist.
But the creation of the GEMIN4-Luc stable cell line was technically difficult, so we make ChoRE-Luc stable cell line in parallel, it was ssuccessful.Using these cell line, we proceeded high-throughput screening (HTS) using an onset of and finally two hit compounds are obtained. We delivered these compounds to iNOS transgenic (TG) mouse and examined the albumin urine output and compared pharmacological effect with other drugs.

Academic Significance and Societal Importance of the Research Achievements

糖尿病性腎症の治療薬は、これまでもレニン-アンジオテンシン-アルドステロン系（RAAS）阻害薬が使用されてきたが、アルドステロン・ブロックの腎保護作用の機序に関しては未だ十分には解明されていない。本研究ではGEMIN4といったMR受容体のCorepressorを標的にした新規創薬目指したが、技術的に困難であった。しかし並行して進めていた、血糖に応答するChoREといった別の転写因子を制御する物質を絞り込め、1型糖尿病性腎症モデルへの投与で尿蛋白減少効果を確認でき、腎メサンギウム細胞に発現する転写因子の制御による糖尿病性腎症治療といった新たな可能性を提示できたという点で意義があったと考えられる。

Research Products

• [Journal Article] High glucose stimulates expression of aldosterone synthase (CYP11B2) and secretion of aldosterone in human adrenal cells (2017)
  • Author(s): Shimada Hiroki、Kogure Naotaka、Noro Erika、Kudo Masataka、Sugawara Kaori、Sato Ikuko、Shimizu Kyoko、Kobayashi Makoto、Suzuki Dai、Parvin Rehana、Saito-Ito Takako、Uruno Akira、Saito-Hakoda Akiko、Rainey William E.、Ito Sadayoshi、Yokoyama Atsushi、Sugawara Akira
  • Journal Title: FEBS Open Bio Volume: 7 Issue: 9 Pages: 1410-1421
  • DOI: 10.1002/2211-5463.12277
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 糖尿病性腎症とミネラロコルチコイド受容体 (2017)
  • Author(s): 工藤正孝、菅原明
  • Journal Title: BIO Clinica Volume: 32 Pages: 97-101
• [Presentation] Effect of Autonomous Cortisol Secretion on Cerebrovasuclular Events in Patients with Primary Aldosteronism (2018)
  • Author(s): Masataka Kudo, Shunji Mugikura, Ryo Morimoto, Yuta Tezuka, Kei Omata, Beata Shiratori, Yasuhiro Igarashi, Kazumasa Seiji, Kei Takase, Sadayoshi Ito and Fumitoshi Satoh
  • Organizer: AHA Council on Hypertension American Society of Hypertension Joint Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] Cerebrovasuclular Events in Patients with Primary Aldosteronism: Results of the PA Sendai Study registry (2017)
  • Author(s): Masataka Kudo, Shunji Mugikura, Ryo Morimoto, Yuta Tezuka, Kei Omata, Mashiro Nezu, Yasuhiro Igarashi, Kazumasa Seiji, Kei Takase, Sadayoshi Ito and Fumitoshi Satoh
  • Organizer: AHA Council on Hypertension American Society of Hypertension Joint Scientific Sessions 2017
  • Int'l Joint Research