Application for treatments of chronic kidney disease used by podocyte specific transcription factor MafB

2019 Fiscal Year Final Research Report

• Project/Area Number: 19K21330
• Project/Area Number (Other): 18H06230 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0904:Internal medicine of the bio-information integration and related fields
• Research Institution: University of Tsukuba
• Principal Investigator: Usui Toshiaki 筑波大学, 医学医療系, 講師 (50825099)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Keywords: 糸球体上皮細胞 / MafB / 転写因子 / 慢性腎臓病 / 巣状分節性糸球体硬化症 / 誘導剤 / atRA

Outline of Final Research Achievements

The analysis for an accepted murine model for focal segmental glomerulosclerosis (FSGS), the level of urinary protein in MafB podocyte-specific transgenic (TG) mice was significantly less than in wild-type mice.In addition, the renal damage in TG mice was ameliorated. We already showed that All-trans retinoic acid (atRA), one of vitamin-A derivative, activates Mafb expression in macrophages. We found that atRA induced Mafb expression in cultured murine podocytes in a dose-dependent manner. Next, we investigated the effects of atRA on murine model for FSGS. Glomerular Mafb expression was significantly increased in atRA-treated mice. The level of urinary protein in atRA-treated mice was significantly lower than in atRA-non-treated mice and the renal damage in atRA-treated mice was ameliorated. MafB genetic over expression in podocytes or the MafB inducer protects again FSGS in mice.

Free Research Field

腎臓内科学

Academic Significance and Societal Importance of the Research Achievements

巣状分節性糸球体硬化症は、指定難病の対象となっている疾患で、治療にはステロイド剤や免疫抑制薬が用いられるが、難治性で、患者の約4割が、発症後15年程度で末期腎不全に至る。主として糸球体上皮細胞の傷害が、巣状分節性糸球体硬化症の発症・進展の鍵を握ると考えられているが、これまで発症メカニズムは十分に解明されていなかった。
今回の研究において、遺伝子操作や既存の白血病治療薬（オールトランスレチノイン酸）投与により、糸球体上皮細胞にMafBを過剰発現させたマウスでは、腎障害悪化やタンパク尿が軽減することを解明した。この結果は、巣状分節性糸球体硬化症の新しい治療法開発の基盤となる。