Analysis of mechanisms of tubulointerstitial injury by renal mononuclear phagocytes.

• Project/Area Number: 18K08231
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Gunma University
• Principal Investigator: Hiromura Keiju 群馬大学, 大学院医学系研究科, 教授 (70292597)
• Co-Investigator(Kenkyū-buntansha): 金子 和光 群馬大学, 医学部附属病院, 講師 (00334095)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 腎臓病学 / 尿細管間質障害 / 腎線維化 / 腎単核貪食細胞 / 腎臓病 / 腎不全 / 腎単核食細胞 / 樹状細胞 / マクロファージ / 腎尿細管間質障害

Outline of Final Research Achievements

CD11c-specific Shp1-deficient mice (Shp1-CKO mice) spontaneously develop tubulointerstitial nephritis with aging. We found that CD11c+F4/80high renal mononuclear phagocytes proliferate and transform into α-SMA-positive myofibroblasts in this process. CD11c+F4/80high renal mononuclear phagocytes from Shp1-CKO mice showed robust cell proliferation by M-CSF stimulation, together with enhancement and prolongation of phosphorylation of M-CSF receptor. These results suggest that Shp1 may negatively regulate the proliferation of CD11c+F4/80high renal mononuclear phagocytes and the transformation into myofibroblasts.

Academic Significance and Societal Importance of the Research Achievements

尿細管間質障害は末期腎不全への進行過程で共通にみられる病態である。特に尿細管間質の線維化は多くが非可逆的であり、その制御は末期腎不全への進展阻止のために重要である。今回の研究より、腎単核貪食細胞は腎尿細管線維化に直接的に関与する細胞群であること、ならびに腎単核食細胞の増殖や形質転換にチロシンホスファターゼであるShp1が深く関与している可能性があることを示した。今後、Shp1経路の制御による腎障害進展阻止に向けた研究の進展が期待される。

Research Products

• [Journal Article] Importance of methodology in the evaluation of renal mononuclear phagocytes and analysis of a model of experimental nephritis with Shp1 conditional knockout mice (2020)
  • Author(s): Watanabe Mitsuharu、Kaneko Yoriaki、Ohishi Yuko、Kinoshita Masato、Sakairi Toru、Ikeuchi Hidekazu、Maeshima Akito、Saito Yasuyuki、Ohnishi Hiroshi、Nojima Yoshihisa、Matozaki Takashi、Hiromura Keiju
  • Journal Title: Biochemistry and Biophysics Reports Volume: 22 Pages: 100741-100741
  • DOI: 10.1016/j.bbrep.2020.100741
  • Peer Reviewed / Open Access
• [Presentation] 腎単核食細胞の解析においては細胞の単離法が重要である (2020)
  • Author(s): 渡辺光治, 金子和光, 今井陽一, Shreya Shrestha, 木下雅人, 大石裕子, 坂入徹, 池内秀和, 野島美久, 廣村桂樹
  • Organizer: 第63回日本腎臓学会学術集会総会
• [Presentation] CD11c陽性細胞に特異的なShp-1の欠損は腎単核食細胞を活性化し腎の線維化を促進する (2019)
  • Author(s): 渡辺光治, 金子和光, 木下雅人, 大石裕子, 坂入 徹, 池内秀和, 野島美久, 廣村桂樹
  • Organizer: 第62回日本腎臓学会総会
• [Presentation] Establishment of a Preparative Method and Gating Strategy for Renal Mononuclear Phagocytes (rMophs) and Analysis of rMophs in CD11c-Specifc Shp-1 Knockout Mice (2019)
  • Author(s): Watanabe M, Kaneko Y, Kinoshita M, Shrestha S, Ohishi Y, Sakairi T, Ikeuchi H, Nojima Y, Hiromura K
  • Organizer: Annual Meeting of American Society of Nephrology 2019
  • Int'l Joint Research
• [Presentation] CD11c-Specific Ablation of SHP-1 Results in Renal Fibrosis with Age (2018)
  • Author(s): Watanabe M, Kaneko Y, Kinoshita M, Ohishi Y, Sakairi T, Ikeuchi H, Nojima Y, Hiromura K
  • Organizer: Annual Meeting of American Society of Nephrology 2018
  • Int'l Joint Research