Nampt regulates extracellular matrix composition in DKD
| Project/Area Number |
19K08732
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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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| Review Section |
Basic Section 53040:Nephrology-related
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| Research Institution | The University of Tokushima (2021)
Keio University (2019-2020) |
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Principal Investigator |
HASEGAWA Kazuhiro 徳島大学, 大学院医歯薬学研究部(医学域), 准教授 (30424162)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | Nampt / NMN / NAD |
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| Outline of Research at the Start |
既に作出した NamptCKOで広範な TBM(tubular basement membrane) 肥 厚 ＝ 尿細管基底膜肥厚 （PAM） 、線維化（マッソン）を認め、type IV collagen 増生がその実態である事まで同定できた。倫理審査認可の下、原因が糖尿病と明らかな為、本来施行例が限られるヒト糖尿病性腎臓病 腎生検も積極的に施行し、多数標本を採取しているが、これらでも重要な事に Nampt 低下と線維化が強相関した。今後、Nampt 低下が type IV collagen を増生する分子機序の詳細を同定し、新規医薬の標的分子としての意義を確立したい。
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| Outline of Final Research Achievements |
Nicotinamide adenine dinucleotide (NAD+) metabolism plays a critical role in kidneys. We previously reported that decreased secretion of a NAD+ precursor, nicotinamide mononucleotide (NMN), from proximal tubules (PTs) can trigger diabetic albuminuria. We investigated the role of NMN-producing enzyme nicotinamide phosphoribosyltransferase (Nampt) in diabetic nephropathy. The expression of Nampt in PTs was downregulated in streptozotocin (STZ)-treated diabetic mice when they exhibited albuminuria. This albuminuria was ameliorated in PT-specific Nampt-overexpressing transgenic (TG) mice. PT-specific Nampt-conditional knockout (Nampt CKO) mice exhibited TBM thickening and collagen deposition, which were associated with the upregulation of the profibrogenic gene TIMP-1. Nampt CKO mice also exhibited the downregulation of sirtuins, particularly in Sirt6. In conclusion, the Nampt-Sirt6 axis in PTs serves as a key player in fibrogenic extracellular matrix remodeling in diabetic nephropathy.
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| Academic Significance and Societal Importance of the Research Achievements |
透析の最大の原疾患である糖尿病性腎症（Diabetic Nephopathy, DN）は、透析のみならず、心血管合併症を引き起こし、生命予後を不良にするばかりか、これらの治療に要する医療費を増大させるため、社会的悪影響が大きい。糖尿病性腎症は、今もって糖尿病や高血圧への治療が中心であり、腎そのものへの有効な治療法は今もって存在しないことが、増え続ける一方の患者数と医療費増大に歯止めが利かない理由である。Namptの糖尿病性腎症における生体意義を明らかにした我々の今回の研究成果を今後さらに発展させることで、Nampt低下を抑止する治療薬への開発につながり得る学術的、社会的波及効果が考えられる。
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Report
(4 results)
Research Products
(10 results)
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[Journal Article] Pre-emptive Short-term Nicotinamide Mononucleotide Treatment in a Mouse Model of Diabetic Nephropathy.2021
Author(s)
Yasuda I, Hasegawa K, Sakamaki Y, Muraoka H, Kawaguchi T, Kusahana E, Ono T, Kanda T, Tokuyama H, Wakino S, Itoh H.
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Journal Title
J Am Soc Nephrol
Volume: 11
Issue: 6
Pages: 1355-1370
DOI
Related Report
Peer Reviewed
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