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Chop deficiency prevents UUO-induced renal fibrosis by attenuating fibrotic
signals originated from Hmgb1/TLR4/NF?B/IL-1? signaling
#MMPMID26247732
Zhang M
; Guo Y
; Fu H
; Hu S
; Pan J
; Wang Y
; Cheng J
; Song J
; Yu Q
; Zhang S
; Xu JF
; Pei G
; Xiang X
; Yang P
; Wang CY
Cell Death Dis
2015[Aug]; 6
(8
): e1847
PMID26247732
show ga
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?B signaling, which then repressed
UUO-induced IL-1? production. Consequently, the IL-1? downstream Erk1/2 activity
and its related c-Jun transcriptional activity were reduced, leading to
attenuated production of TGF-?1 following UUO insult. It was further noted that
reduced IL-1? 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.
|Animals
[MESH]
|Apoptosis/genetics
[MESH]
|Fibrosis
[MESH]
|Gene Expression Regulation
[MESH]
|HMGB1 Protein/*genetics/metabolism
[MESH]
|Humans
[MESH]
|Interleukin-1beta/*genetics/metabolism
[MESH]
|JNK Mitogen-Activated Protein Kinases/genetics/metabolism
[MESH]
|Kidney/metabolism/pathology
[MESH]
|Mice
[MESH]
|Mice, Inbred C57BL
[MESH]
|Mice, Knockout
[MESH]
|Mitogen-Activated Protein Kinase 1/genetics/metabolism
[MESH]
|Mitogen-Activated Protein Kinase 3/genetics/metabolism
[MESH]
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