期刊
CELL DEATH & DISEASE
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2015.206
关键词
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类别
资金
- National Natural Science Foundation of China [81130014, 81471046, 81428001]
- program for Changjiang Scholars and Innovative Research Team in University [IRT_14R20]
- European Foundation for the Study of Diabetes (EFSD)/Chinese Diabetes Society (CDC)/Lilly Program for Collaborative Diabetes Research between China and Europe
- Tongji Hospital
Renal fibrosis, particularly tubulointerstitial fibrosis is considered to be the final manifestation of almost all chronic kidney diseases (CKDs). Herein we demonstrated evidence that CHOP-related ER stress is associated with the development of renal fibrosis in both CKD patients and unilateral ureteral obstruction (UUO)-induced animals, and specifically, mice deficient in Chop were protected from UUO-induced renal fibrosis. Mechanistic studies revealed that loss of Chop protected tubular cells from UUO-induced apoptosis and secondary necrosis along with attenuated Hmgb1 passive release and active secretion. As a result, Chop deficiency suppressed Hmgb1/TLR4/NF kappa B signaling, which then repressed UUO-induced IL-1 beta production. Consequently, the IL-1 beta downstream Erk1/2 activity and its related c-Jun transcriptional activity were reduced, leading to attenuated production of TGF-beta 1 following UUO insult. It was further noted that reduced IL-1 beta production also inhibited UUO-induced PI3K/AKT signaling, and both of which ultimately protected mice from UUO-induced renal fibrosis. Together, our data support that suppression of CHOP expression could be a viable therapeutic strategy to prevent renal fibrosis in patients with CKDs.
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