title: Chop deficiency prevents UUO-induced renal fibrosis by attenuating fibrotic signals originated from Hmgb1/TLR4/NFκB/IL-1β signaling.
abstract: 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/NFκB signaling, which then repressed UUO-induced IL-1β production. Consequently, the IL-1β downstream Erk1/2 activity and its related c-Jun transcriptional activity were reduced, leading to attenuated production of TGF-β1 following UUO insult. It was further noted that reduced IL-1β 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.
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: H
authors.initials: H
authors.lastname: Fu
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: S
authors.initials: S
authors.lastname: Hu
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: J
authors.initials: J
authors.lastname: Pan
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: J
authors.initials: J
authors.lastname: Cheng
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: J
authors.initials: J
authors.lastname: Song
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Yu
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical College, Dongguan, China.
authors.forename: J-F
authors.initials: JF
authors.lastname: Xu
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: G
authors.initials: G
authors.lastname: Pei
authors.affiliation: Department of Emergency Medicine, Institute of Emergency Medicine and Rare Diseases, The Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: X
authors.initials: X
authors.lastname: Xiang
authors.affiliation: The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: P
authors.initials: P
authors.lastname: Yang
authors.affiliation: 1] The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China [2] Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical College, Dongguan, China [3] Department of Emergency Medicine, Institute of Emergency Medicine and Rare Diseases, The Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D005355:Fibrosis; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009336:Necrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009395:Nephritis, Interstitial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000172:deficiency / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014517:Ureteral Obstruction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C497250:Ddit3 protein, mouse; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D053583:Interleukin-1beta; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053773:Transforming Growth Factor beta1; D051742:Transcription Factor CHOP; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3