Inhibition of JMJD3 attenuate renal senescense in ischemic reperfusion mice
| Project/Area Number |
16K09618
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Kidney internal medicine
|
|---|
| Research Institution | Hiroshima University |
|---|
Principal Investigator |
Doi Shigehiro 広島大学, 病院(医), 病院助教 (80626127)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
正木 崇生 広島大学, 病院(医), 教授 (30397913)
中島 歩 広島大学, 医歯薬保健学研究科(医), 共同研究講座教授 (40448262)
|
|---|
| Research Collaborator |
UENO Toshinori
SASAKI Kensuke
SHIMODA Hironori
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
|
|---|
| Keywords | MLL1 / WDR5 / H3K4me3 / p16INK4a / Senescence / Acute kidney injury / 老化 / p16 / 虚血再灌流障害 / 線維化 / ヒストンメチル化 / ヒストンメチル化酵素 / 腎線維化 |
|---|
| Outline of Final Research Achievements |
MM-102 suppressed expression of p16INK4a and β-gal in ischemic reperfusion injury (IRI) mice, accompanied by decreased expression of Mixed-lineage leukemia 1 (MLL1) and WD-40 repeat protein 5 (WDR5) as well as H3K4me3. MM-102 also attenuated renal fibrosis and inflammation in the kidneys of IRI mice. In the in vitro study, transforming growth factor-β1 induced expression of MLL1, WDR5, H3K4me3 and p16INK4a. Finally, the p16INK4a promoter was revealed to be an H3K4me3 site in renal fibroblasts.In conclusion, the MLL1/WDR5 inhibitor MM-102 ameliorates IRI-induced renal senescence together with renal fibrosis and inflammation through a reduction in H3K4me3.
|
| Academic Significance and Societal Importance of the Research Achievements |
本研究において、腎障害によって惹起されるMixed-lineage leukemia 1 (MLL1)とWD-40 repeat protein 5 (WDR5)の発現亢進によって、H3K4のトリメチル化が起こる結果、腎臓の老化が誘導され、腎における慢性炎症や線維化という病態をきたすことを証明された。この結果、なぜ慢性腎臓病（CKD）における臨床的、病理学的特徴は、加齢腎と一致するのかということが明らかにされた。さらに、CKDを治療する際には、老化に対しても介入しなければ、その進展を完全に抑制することはできないことも認識される。
|
Report
(4 results)
Research Products
(2 results)
