Published online before print June 18, 2009

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(American Journal of Pathology. 2009;175:74-83.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080884

Decrease in Tumor Necrosis Factor- Receptor-Associated Death Domain Results from Ubiquitin-Dependent Degradation in Obstructive Renal Injury in Rats

Taro Misaki^*, Tatsuo Yamamoto, Sayuri Suzuki^*, Hirotaka Fukasawa^*, Akashi Togawa^*, Naro Ohashi^*, Hiroyuki Suzuki^*, Yoshihide Fujigaki^*, Toshiaki Oda, Chiharu Uchida, Kyoko Kitagawa, Takayuki Hattori, Masatoshi Kitagawa and Akira Hishida^*

From the First Department of Medicine,^* and the Department of Biochemistry 1, Hamamatsu University School of Medicine; and the Department of Health and Nutritional Sciences, Hamamatsu University, Hamamatsu, Japan

Increased expression levels of tumor necrosis factor- (TNF) is involved in tubulointerstitial cell proliferation and apoptosis in obstructive renal injury. Two TNF receptors (TNFRs), TNFR1 and TNFR2, are known to exist. On TNF binding, TNFR1 recruits TNFR-associated death domain (TRADD), an assembly platform to mediate TNFR1 signaling. We investigated postreceptor TRADD regulation in rat kidneys with unilateral ureteral obstruction (UUO). Whereas UUO was associated with increased expression levels of TNF, TNFR1, TNFR2, and TRADD mRNAs, it resulted in the marked decrease of TRADD protein levels (which appeared at day 1 and persisted thereafter) and a slight decrease in TNFR1 protein levels at days 7 and 14. Both ubiquitination and degradation of TRADD were increased in UUO kidneys, degradation of TRADD was stimulated by TNF in HK-2 cells, and TRADD degradation was suppressed by proteasome inhibitor. Inhibition of TNF 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 into TNFR2-mediated TNF signaling, the persistent decrease in TRADD, associated with a mild decrease in TNFR1 levels, may function, at least in part, to divert TNF signals toward a TNFR2-mediated pathway in UUO kidneys.