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Decrease in tumor necrosis factor-alpha receptor-associated death domain results from ubiquitin-dependent degradation
Taro Misaki1, Tatsuo Yamamoto, Sayuri Suzuki
1Department of Health and Nutritional Sciences, Faculty of Health Promotional Sciences, Hamamatsu University, Hamamatsu, Japan.
The American Journal of Pathology
|June 23, 2009
Summary
In obstructive renal injury, tumor necrosis factor-alpha (TNFalpha) signaling is altered. Enhanced degradation of TRADD protein, a key signaling molecule, contributes to kidney damage by diverting signals toward TNFR2.
Area of Science:
- Nephrology
- Molecular Biology
- Immunology
Background:
- Obstructive renal injury involves increased tumor necrosis factor-alpha (TNFalpha) expression, impacting tubulointerstitial cells.
- Two TNFalpha receptors, TNFR1 and TNFR2, mediate distinct signaling pathways.
- TNFR1 signaling involves the recruitment of TNFR-associated death domain (TRADD).
Purpose of the Study:
- To investigate the post-receptor regulation of TRADD in rat kidneys with unilateral ureteral obstruction (UUO).
- To elucidate the role of TRADD degradation in the pathogenesis of obstructive renal injury.
Main Methods:
- UUO model in rats to assess mRNA and protein levels of TNFalpha, TNFR1, TNFR2, and TRADD.
- Analysis of TRADD ubiquitination and degradation in kidney tissues and HK-2 cells.
- Treatment with etanercept (soluble TNFR2) to evaluate its effect on renal injury markers and TRADD degradation.
Main Results:
- UUO increased TNFalpha, TNFR1, TNFR2, and TRADD mRNA, but decreased TRADD and TNFR1 protein levels.
- TRADD ubiquitination and degradation were significantly increased in UUO kidneys, stimulated by TNFalpha and mediated by the proteasome.
- Etanercept treatment reduced cell proliferation, fibronectin expression, and apoptosis in UUO kidneys, and suppressed TRADD degradation.
Conclusions:
- Enhanced ubiquitin-dependent degradation of TRADD contributes to obstructive renal injury.
- The persistent decrease in TRADD may redirect TNFalpha signaling towards the TNFR2 pathway.
- Targeting TNFalpha signaling offers a potential therapeutic strategy for obstructive renal injury.
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