Decrease in tumor necrosis factor-alpha receptor-associated death domain results from ubiquitin-dependent degradation in obstructive renal injury in rats.
Increased expression levels of tumor necrosis factor-alpha (TNFalpha) is involved in tubulointerstitial cell proliferation and apoptosis in obstructive renal injury. Two TNFalpha receptors (TNFRs), TNFR1 and TNFR2, are known to exist. On TNFalpha 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 TNFalpha, 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 TNFalpha in HK-2 cells, and TRADD degradation was suppressed by proteasome inhibitor. Inhibition of TNFalpha 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 TNFalpha signaling, the persistent decrease in TRADD, associated with a mild decrease in TNFR1 levels, may function, at least in part, to divert TNFalpha signals toward a TNFR2-mediated pathway in UUO kidneys.
Misaki
Taro
T
Department of Health and Nutritional Sciences, Faculty of Health Promotional Sciences, Hamamatsu University, Hamamatsu, Japan.
Yamamoto
Tatsuo
T
Suzuki
Sayuri
S
Fukasawa
Hirotaka
H
Togawa
Akashi
A
Ohashi
Naro
N
Suzuki
Hiroyuki
H
Fujigaki
Yoshihide
Y
Oda
Toshiaki
T
Uchida
Chiharu
C
Kitagawa
Kyoko
K
Hattori
Takayuki
T
Kitagawa
Masatoshi
M
Hishida
Akira
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D000068800:Etanercept; D006801:Humans; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000494:pharmacology; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054875:Ubiquitination; D014517:Ureteral Obstruction / Q000150:complications
D007074:Immunoglobulin G; D007155:Immunologic Factors; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D053199:TNF Receptor-Associated Death Domain Protein; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept