The efficacy of RAGE-DNA aptamer for prevention of hypertensive nephropathy

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K16106
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Kurume University
• Principal Investigator: TAGUCHI KENSEI 久留米大学, 医学部, 助教 (10647738)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: ループス腎炎 / RAGEアプタマー / 尿細管障害

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.

Free Research Field

ループス腎炎

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。