DNA methylation and hydroxymethylation in the kidney from offspring of nutrient restricted rats

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K10152
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Keio University
• Principal Investigator: AWAZU Midori 慶應義塾大学, 医学部(信濃町), 講師(非常勤) (20129315)
• Co-Investigator(Kenkyū-buntansha): 飛彈 麻里子 慶應義塾大学, 医学部(信濃町), 准教授 (20276306)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 腎発生 / 母体低栄養 / エピジェネティクス / DNAヒドロキシメチル化 / 酸化ストレス / Tet / Sod3

Outline of Final Research Achievements

Global DNA hydroxymethylation and the expression of Tet proteins (Tet1, Tet2, Tet3) of metanephroi of offspring from nutrient-restricted rat dams (NR) were increased compared with control metanephroi. In organ culture, metanephroi exposed to ascorbic acid that facilitates Tet enzyme activity had significantly decreased ureteric bud tip number compared with controls. Dimethyloxallyl glycine, a small-molecule inhibitor of Tet, significantly decreased both ureteric bud branching and kidney size. We further identified Sod3 as a gene, whose hydroxymethylation was increased in NR. mRNA expression of Sod3 was decreased in NR. Sod3 is known to prevent the progression of chronic kidney disease and to protect mesenchymal stem cells from various stresses including nutrient deficiency and oxidative stress. Sod3 may play a role in low nephron number as well as aggravated tubular necrosis and fibrosis after unilateral ureteral obstruction in NR, which we previously reported.

Free Research Field

小児科学、腎臓学

Academic Significance and Societal Importance of the Research Achievements

母体低栄養モデルラットにおけるネフロン数減少、および生後の二次侵襲による尿細管壊死、間質線維化の原因としてエピジェネティクス機構の関与が明らかになった。これにより現在問題となっている低出生体重児の増加、その結果としての慢性腎臓病を含む生活習慣病増加に対する予防、治療への対策の可能性が開かれた。