2009 Fiscal Year Final Research Report
Mechanism of Tumor Necrosis Factorα signaling in renal injury
| Project/Area Number |
20790591
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Kidney internal medicine
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| Research Institution | Hamamatsu University School of Medicine |
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Principal Investigator |
MISAKI Taro Hamamatsu University School of Medicine, 医学部附属病院, 医員 (20464125)
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| Project Period (FY) |
2008 – 2009
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| Keywords | 細胞内シグナル伝達 |
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| Research Abstract |
Increased expression of tumor necrosis factor-α (TNFα) is involved in tubulointerstitial cell proliferation and apoptosis in obstructive renal injury. Two TNFα receptors (TNFR), TNFR1 and TNFR2, exist. On TNFα binding, TNFR1 recruits TNFR-associated death domain (TRADD), an assembly platform to diverge TNFR1 signaling. The precise mechanism of TNFR2-mediated signaling is not fully elucidated. We investigated post-receptor TRADD regulation in rat kidneys with unilateral ureteral obstruction (UUO). Whereas UUO was associated with increased expression of TNFα, TNFR1, TNFR2, and TRADD mRNAs, TRADD protein decreased markedly at day 1 and remained to be low thereafter, which was associated with a slight decrease in TNFR1 protein levels at days 7 and 14. Ubiquitination and degradation of TRADD were increased in UUO kidneys, degradation of TRADD was stimulated by TNFα in HK-2 cells, and its degradation was suppressed by proteasome inhibitor. Inhibition of TNFα by soluble TNFR2, etanercept, reduced significantly, although transiently, tubular and interstitial cell proliferation, fibronectin expression, and apoptosis in UUO kidneys, and also suppressed TRADD degradation. These data suggest that the decrease in TRADD resulting from enhanced ubiquitin-dependent degradation is involved in obstructive renal injury. Since TRADD is not incorporated in TNFR2-mediated TNFα signaling, the sustained decrease in TRADD may function, at least in part, to divert TNFα signals toward a TNFR2-mediated pathway in UUO kidneys.
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[Journal Article] Decrease in TRADD resulted from ubiquitin-dependent degradation in the obstructive renal injury in rats2009
Author(s)
Misaki T, Yamamoto T, Suzuki S, Fukasawa H, Togawa A, Ohashi N, Suzuki H, Fujigaki Y, Oda T, Uchida C, Kitagawa K, Hattori T, Kitagawa M, Hishida A
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Journal Title
Am J Pathol 175(1)
Pages: 74-83
Peer Reviewed
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