BMAL1 inhibits renal fibrosis and renal interstitial inflammation by targeting the ERK1/2/ELK-1/Egr-1 axis

被引:9
作者
Chen, Wu [1 ]
Zhao, Sheng [1 ]
Xing, Ji [1 ]
Zhou, Xiangjun [1 ]
Li, Siqi [1 ,2 ]
Xia, Yuqi [1 ]
Song, Tianbao [1 ]
Li, Wei [2 ]
Zou, Fan [1 ]
Cheng, Fan [1 ]
机构
[1] Wuhan Univ, Dept Urol, Renmin Hosp, Wuhan 430060, Peoples R China
[2] Wuhan Univ, Dept Anesthesiol, Renmin Hosp, Wuhan 430060, Peoples R China
基金
中国国家自然科学基金;
关键词
BMAL1; UUO; Renal fibrosis; Renal interstitial inflammation; ERK1/2/ELK-1/Egr-1; pathway; CIRCADIAN GENE-EXPRESSION; MECHANISMS; TRANSCRIPTION; STRESS;
D O I
10.1016/j.intimp.2023.111140
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Rationale: Renal fibrosis and renal interstitial inflammation due to hydronephrosis are associated with progressive chronic kidney disease (CKD). The clock gene BMAL1 is thought to be involved in various diseases, including hypertension, diabetes, etc. However, little is known about how BMAL1 regulates renal fibrosis and renal interstitial inflammation in obstructed kidneys.Methods: The expression level of BMAL1 in UUO was examined using the GEO database. Lentivirus, siRNA and adeno-associated virus were used to modulate BMAL1 levels in HK-2 cells and mouse kidney. qRT-PCR, immunofluorescence staining, histological analysis, ELISA and Western blot were used to determine the level of fibrin deposition and the release of inflammatory factors. Immunofluorescence staining and western blotting were used to examine the interaction between BMAL1 and the ERK1/2/ELK-1/Egr-1 axis.Results: Bioinformatics analysis and in vivo experiments in this study showed that the expression level of BMAL1 in UUO model kidneys was higher than that in normal kidneys. We then found that downregulation of BMAL1 promoted the production of extracellular matrix (ECM) proteins and proinflammatory factors in vivo and in vitro, whereas upregulation inhibited this process. In addition, we demonstrated that the ERK1/2/ELK-1/Egr-1 axis is an important pathway for BMAL1 to play a regulatory role, and the use of PD98059 abolished the promoting effect of down-regulation of BMAL1 on fibrosis and inflammation.Conclusions: Our findings suggest that BAML1 can target the ERK1/2/ELK-1/Egr-1 axis to suppress fibrotic progression and inflammatory events in obstructed kidneys, thereby inhibiting the development of CKD.
引用
收藏
页数:15
相关论文
共 42 条
[1]   Circadian Rhythm Protein Bmal1 Modulates Cartilage Gene Expression in Temporomandibular Joint Osteoarthritisviathe MAPK/ERK Pathway [J].
Chen, Guokun ;
Zhao, Haoming ;
Ma, Shixing ;
Chen, Lei ;
Wu, Gaoyi ;
Zhu, Yong ;
Zhu, Jie ;
Ma, Chuan ;
Zhao, Huaqiang .
FRONTIERS IN PHARMACOLOGY, 2020, 11
[2]   Matrix Stiffening Enhances DNCB-Induced IL-6 Secretion in Keratinocytes Through Activation of ERK and PI3K/Akt Pathway [J].
Chung, Hyewon ;
Oh, Seunghee ;
Shin, Hyun-Woo ;
Lee, Yunam ;
Lee, Hyungsuk ;
Seok, Seung Hyeok .
FRONTIERS IN IMMUNOLOGY, 2021, 12
[3]   Differences in renal BMAL1 contribution to Na+ homeostasis and blood pressure control in male and female mice [J].
Crislip, G. Ryan ;
Douma, Lauren G. ;
Masten, Sarah H. ;
Cheng, Kit-Yan ;
Lynch, I. Jeanette ;
Johnston, Jermaine G. ;
Barral, Dominique ;
Glasford, Krystal B. ;
Holzworth, Meaghan R. ;
Verlander, Jill W. ;
Wingo, Charles S. ;
Gumz, Michelle L. .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2020, 318 (06) :F1463-F1477
[4]   Regulation of transforming growth factor-beta1 (TGF-β1)-induced pro-fibrotic activities by circadian clock gene BMAL1 [J].
Dong, Chunmin ;
Gongora, Rafael ;
Sosulski, Meredith L. ;
Luo, Fayong ;
Sanchez, Cecilia G. .
RESPIRATORY RESEARCH, 2016, 17
[5]   The origin of scar-forming kidney myofibroblasts [J].
Eddy, Allison A. .
NATURE MEDICINE, 2013, 19 (08) :964-966
[6]   Transcriptional Characteristics of Activated Macrophages [J].
Glanz, Victor ;
Myasoedova, Veronika A. ;
Sukhorukov, Vasily ;
Grechko, Andrey ;
Zhang, Dongwei ;
Romaneneko, Elena B. ;
Orekhova, Varvara A. ;
Orekhov, Alexander .
CURRENT PHARMACEUTICAL DESIGN, 2019, 25 (03) :213-217
[7]   Ribes diacanthum Pall (RDP) ameliorates UUO-induced renal fibrosis via both canonical and non-canonical TGF-β signaling pathways in mice [J].
Gu, Lifei ;
Wang, Yange ;
Yang, Guolin ;
Tilyek, Akhtolkhyn ;
Zhang, Chunlei ;
Li, Shaoheng ;
Yu, Boyang ;
Chai, Chengzhi ;
Cao, Zhengyu .
JOURNAL OF ETHNOPHARMACOLOGY, 2019, 231 :302-310
[8]   International comparison of the relationship of chronic kidney disease prevalence and ESRD risk [J].
Hallan, Stein I. ;
Coresh, Josef ;
Astor, Brad C. ;
Asberg, Arne ;
Powe, Neil R. ;
Romundstad, Solfrid ;
Hallan, Hans A. ;
Lydersen, Stian ;
Holmen, Jostein .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2006, 17 (08) :2275-2284
[9]   Mechanisms of Renal Fibrosis [J].
Humphreys, Benjamin D. .
ANNUAL REVIEW OF PHYSIOLOGY, VOL 80, 2018, 80 :309-326
[10]   Loss of myeloid Bmal1 exacerbates hypertensive vascular remodelling through interaction with STAT6 in mice [J].
Huo, Mingyu ;
Cao, Xiaoyun ;
Zhang, Hongsong ;
Lau, Chi Wai ;
Hong, Huiling ;
Chen, Francis M. ;
Huang, Yu ;
Chawla, Ajay ;
Tian, Xiao Yu .
CARDIOVASCULAR RESEARCH, 2022, 118 (13) :2859-2874