| Project/Area Number |
17K09861
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Okayama University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | メタボリックシンドローム / 近位尿細管細胞 / 慢性腎臓病 / バスピン / Vaspin / アディポカイン / 腎障害 / 近位尿細管 |
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| Outline of Final Research Achievements |
Obesity and diabetes cause proximal tubular cells (PTCs) injury via excessive organelle stresses. In present study, we revealed unique mechanism of PTCs injury induced by palmitate and chemical ER stressor. In HK2 cells, palmitate, tunicamycin and thapsigargin promoted lysosomal membrane permeabilization, leakage of cathepsin B into cytosol, and subsequent NLRP3 inflammasome activation, and ultimately cell death was induced. Vaspin, an adipokine previously we discovered, inhibited this pathway and protected HK2 cells. We newly found that vaspin-interactive molecules, GRP78 and HSPA1L, independently form complex with clathrin heavy chain and both complexes are involved in endocytosis of vaspin. We further identified that intracellular HSPA1L promoted autophagy, and HSPA1L protein level of HK2 cell was decreased by albumin administration accompanied with increased HSPA1L extracellular secretion. Vaspin and HSPA1L may be new therapeutic target to diabetic kidney diseases.
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| Academic Significance and Societal Importance of the Research Achievements |
肥満や糖尿病を背景とした腎障害が増加しているが、予防や治療法の確立はまだ十分とは言えない。そこで、腎予後に強く影響する尿細管間質障害に着目した肥満や糖尿病では、近位尿細管細胞において、細胞内小器官のストレス応答が代償的に亢進しているが、細胞ストレスが過剰であったり、遷延すると非代償的となり細胞死に至る。本研究では、内臓脂肪から分泌される生理活性物質であるバスピンが、近位尿細管細胞の細胞内小器官のストレス応答不全を軽減し、細胞保護的に作用することが明らかにした。
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