2018 Fiscal Year Final Research Report
Nuclear receptor-targeted effective therapy for diabetic glomerulosclerosis through Chip-Seq analysis
| Project/Area Number |
16K19490
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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 | The University of Tokushima |
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Principal Investigator |
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| Research Collaborator |
TOMINAGA Tatsuya
FUJITA Yui
OCHI Arisa
KISHI Seiji
MURAKAMI Taichi
NAGAI Koujiro
ABE Hideharu
DOI Toshio
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | 糖尿病性腎症 / メサンギウム細胞 / 骨形成蛋白質4 / レチノイド / 糖尿病性メサンギウム基質拡大 / RXR/RAR |
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| Outline of Final Research Achievements |
The therapeutic potential of retinoids in diabetic nephropathy (DN) was investigated, focusing especially on the regulatory mechanism of bone morphogenetic protein 4 (BMP4). Glomerular matrix expansion, which was associated with increased BMP4, phosphorylated suppressor of mothers against decapentaplegic (Smad1), and collagen IV (COL4) expression, worsened in streptozotocin-induced diabetic mice at 24 weeks of age. These levels were attenuated after ATRA administration. In cultured mouse mesangial cells, treatment with ATRA or a retinoic acid receptor α (RARα) agonist significantly decreased BMP4 and COL4 expression. ChIP analysis and reporter assays indicated that a putative RARE of the Bmp4 gene, located 11488-11501 bp upstream of exon1A and bound to RARα and retinoid X receptor (RXR), which suppressed BMP4 expression after ATRA addition.
ATRA suppressed BMP4 via binding of a RARα/RXR heterodimer to a unique RARE, alleviating glomerular matrix expansion in diabetic mice.
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| Free Research Field |
腎臓内科
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| Academic Significance and Societal Importance of the Research Achievements |
代表的なレチノイドであるATRAは様々な腎疾患モデルに治療効果を示すが，糖尿病性メサンギウム基質拡大の治療効果は未解明であった。本研究は世界で初めてATRAによる糖尿病性メサンギウム基質拡大治療を報告した。その作用機序として，これまで知られていなかったRXR/RARを介したBMP4制御機構を報告した。本研究成果は十分な治療法が存在しない糖尿病性腎症の，新規治療法開発の一助となり得る。また，ATRAによるBMP4遺伝子制御機構の解明手法は他の遺伝子制御機構の解明にも応用できる可能性がある。
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