Generation of anti-fibrotic therapy to combat progression of CKD via CCN2 blockade

• Project/Area Number: 25461228
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Saitama Medical University
• Principal Investigator: Okada Hirokazu 埼玉医科大学, 医学部, 教授 (60233342)
• Co-Investigator(Kenkyū-buntansha): INOUE Tsutomu 埼玉医科大学, 医学部, 准教授 (30406475)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: CCN2 / 腎線維化 / 遺伝子改変動物 / CKD / 尿細管上皮細胞 / 線維芽細胞 / ノックインマウス

Outline of Final Research Achievements

CCN2 consists of four different functional modules, and the most profibrogenic module remains to be clarified.　Ｗe found a module IV-defective CCN2 did not induce fibronectin synthesis in fibroblasts. Then, we generated Exon 5-deleted CCN2 gene knockin mice, found less kidney fibrosis in those mice with unilateral ureter obstruction and subtotally nephrectomy models. Decoy peptides corresponding to partial amino acid sequences of module IV significantly attenuated renal fibrogenesis. This suggests that CCN2 promotes renal fibrogenesis via its module IV, probably through Integrins-Integrin linked kinase-Akt-GSK3β pathway, which seems to be an appropriate, anti-fibrotic therapeutic target.

Research Products

• [Presentation] Roles of CCN2 and caspase activities in tubular epithelial cells involved in AKI transition to CKD (2015)
  • Author(s): 草野 武
  • Organizer: Kidney Week 2015, the Annual Meeting of the American Society of Nephrology
  • Place of Presentation: San Diego
  • Year and Date: 2015-11-03
  • Int'l Joint Research
• [Presentation] CCN2第4モジュールが腎線維化に重要である (2015)
  • Author(s): 井上勉
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-06-05
• [Presentation] A Module IV-Defective CCN2 Mutant and Module IV-Derived Decoy Peptides Attenuate Renal Fibrogenesis (2014)
  • Author(s): Tsutomu Inoue, MD, PhD, Takeru Kusano, MD, Hiroaki Amano, MD, Kei Sugiyama, MD, Hiromichi Suzuki, MD, PhD, Hirokazu Okada, MD, PhD
  • Organizer: Kidney Week 2014, The annual meeting of the American Society of Nephrology
  • Place of Presentation: Philadelphia Convention Center, Philadelphia, PA, USA
  • Year and Date: 2014-11-13 – 2014-11-16