| Budget Amount *help |
¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2009: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2008: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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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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