| Project/Area Number |
16K09604
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Kidney internal medicine
|
|---|
| Research Institution | The University of Tokyo |
|---|
Principal Investigator |
饒 梓明 東京大学, 医学部附属病院, 助教 (30772446)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
正路 久美 東京大学, 医学部附属病院, その他 (00439423)
川上 貴久 東京大学, 医学部附属病院, 助教 (10722093)
稲城 玲子 東京大学, 医学部附属病院, 准教授 (50232509)
南学 正臣 東京大学, 医学部附属病院, 教授 (90311620)
田中 哲洋 東京大学, 医学部附属病院, 講師 (90508079)
|
|---|
| Project Period (FY) |
2016-04-01 – 2017-03-31
|
| Project Status |
Discontinued (Fiscal Year 2016)
|
| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
|
|---|
| Keywords | Chronic kidney disease / Energy metabolism / UPR / Endoplasmic reticulum / ATF6 / Fatty acid oxidation / Mitochondrial function / kidney fibrosis / kidney / metabolism |
|---|
| Outline of Annual Research Achievements |
Tubular energy depletion is one of the key factors for chronic kidney disease (CKD) progression, especially tubulointerstitial fibrosis. Meanwhile, unfolded protein response (UPR) is essential to maintain endoplasmic reticulum function as well as energy metabolism. However, it is still largely unknown how UPR regulates energy homeostasis and subsequent tubular functions. To address this issue, we overexpressed ATF6, an UPR transcription factor related to energy metabolism, in proximal tubular cells and found that nuclear-translocated active ATF6 (nATF6) reduced mitochondrial respiration and ATP production through downregulation of fatty acid oxidation regulators, including peroxisome proliferator-activated receptor (PPAR), carnitine palmitoyltransferase I, and carnitine palmitoyltransferase II. In addition, such nATF6-mediated mitochondrial dysfunction suppressed tubular cell proliferation in association with induction of apoptotic signaling and G2/M cell cycle arrest. Intriguingly, nATF6 was upregulated in the damaged tubules induced by ischemia-reperfusion or unilateral ureter obstruction in rats. Collectively, we found that ATF6 activation deranged mitochondrial fatty acid metabolism in the tubular cells, leading to tubular apoptosis and cell cycle arrest, both of which may accelerate tubulointerstitial fibrosis. These findings unveiled the role of ATF6 in the tubular energy metabolism. Blockage of overwhelming ATF6 activation or enhancement of PPAR expression could be a therapeutic strategy to retard CKD progression.
|
