Involvement of hsa-miR-143 in podocyte injury by TGF-beta

• Project/Area Number: 16K09601
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Gunma University
• Principal Investigator: Sakairi Toru 群馬大学, 大学院医学系研究科, 助教 (20455976)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: micro-RNA / hsa-miR-143 / 糸球体上皮細胞 / TGF-β / 巣状糸球体硬化症 / 糖尿病性腎症 / TGF-beta1 / micro RNA / TGF-beta / 巣状分節性糸球体硬化症 / マイクロRNA / Wilms tumor 1

Outline of Final Research Achievements

TGF-beta contributes to podocyte injury in FSGS and diabetic nephropathy. MicroRNAs are small non-coding RNAs that repress translation of target mRNAs. We sought to identify miRNAs involved in podocyte injury induced by TGF-beta.
For discovery, we performed miRNA profiling of the cultured human podocytes treated with TGF-beta1using a miRNA microarray. Among miRNAs, hsa-miR-143 had the largest increase. We next performed quantitative RT-PCR, and validated the increase in hsa-miR-143 by TGF-beta. We next assessed the function of hsa-miR-143, using lentiviral expression. TGF-beta1 increased expression of COL1A1 mRNA and decreased that of WT1 mRNA and protein. Ectopic expression of hsa-miR-143 also increased expression of COL1A1 mRNA and decreased expression of WT1 mRNA and protein. In conclusion, TGF-beta1 induced hsa-miR-143 expression in cultured human podocytes and up-regulated hsa-miR-143 may mediate the induction of COL1A1 and the repression of WT1 by TGF-beta1.

Academic Significance and Societal Importance of the Research Achievements

糖尿病性腎症や巣状糸球体硬化症といった難治性の腎臓病の進行にTGF-βが関与していることは以前から知られているが、そのメカニズムは十分には解明されていない。本研究により、TGF-βが、hsa-miR-143の上昇を介して糸球体上皮細胞を障害し、これらの腎臓病を惹起することが示唆された。将来、尿中のhsa-miR-143の測定を行い、これらの腎臓病で上昇することが証明されれば、診断や病勢マーカーとして使用できる可能性がある。更に、miR-143のアンチセンスの導入や、何らかの薬剤によって腎臓内のhsa-miR-143の上昇を抑制することが、将来これらの腎臓病の治療となる可能性がある。