| Project/Area Number |
17K16106
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Kidney internal medicine
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| Research Institution | Kurume University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | ループス腎炎 / RAGEアプタマー / 尿細管障害 / pristane / RAGE / 腎線維化 / エンドサイトーシス / RAGE-DNAアプタマー / ワイヤーループ病変 |
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| Outline of Final Research Achievements |
Urine RAGE concentration was found to be increased over time in MRL-lpr mice, SLE-prone mice. The increase in urine RAGE was also parallel with urine NAG concentration, a marker of tubular damage. To determine whether RAGE-targeting therapy is beneficial for lupus nephritis, we created DNA-aptamer directed against RAGE (RAGE-apt) that can inhibit RAGE function as an antagonist and we injected RAGE-apt into MRL-lpr mice subcutaneously for 8 weeks. The mice treated with RAGE-apt showed the decrease in plasma BUN and IgG and the increase in plasma C3 levels, suggesting that RAGE-apt improved renal dysfunction and immune system abnormality. Histological analysis demonstrated that RAGE-apt reduced the formation of crescent and wire loop lesion and suppressed macrophages infiltration. Further, RAGE-apt reduced the production of inflammatory cytokines in MRL-lpr mice. Therefore, RAGE-apt can become a potent novel therapeutic strategy for inhibiting the progression of lupus nephritis.
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| Academic Significance and Societal Importance of the Research Achievements |
成人SLE患者の約60％でループス腎炎を発症し、LN症例の約25％が発症後10年以内に末期腎不全に至る。加えてステロイド抵抗性LNや長期ステロイド内服による重篤な副作用の存在を考慮すると、新たな治療戦略の創出が急務の課題である。我々はRAGEがSLEモデルマウスで過剰発現しループス腎炎の発症進展に関与していることを突き止めた。次世代分子標的薬であるRAGEアプタマーを作成しSLEモデルマウスで効果を検討した結果、腎機能保護効果が認められ、今後のSLE治療に新たなオプションをもたらすことができると考えられる。
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