title: Circadian CLOCK Mediates Activation of Transforming Growth Factor-β Signaling and Renal Fibrosis through Cyclooxygenase 2.
abstract: The circadian rhythm regulates blood pressure and maintains fluid and electrolyte homeostasis with central and peripheral clock. However, the role of circadian rhythm in the pathogenesis of tubulointerstitial fibrosis remains unclear. Here, we found that the amplitudes of circadian rhythm oscillation in kidneys significantly increased after unilateral ureteral obstruction. In mice that are deficient in the circadian gene Clock, renal fibrosis and renal parenchymal damage were significantly worse after ureteral obstruction. CLOCK-deficient mice showed increased synthesis of collagen, increased oxidative stress, and greater transforming growth factor-β (TGF-β) expression. TGF-β mRNA expression oscillated with the circadian rhythms under the control of CLOCK-BMAL1 heterodimers. The expression of cyclooxygenase 2 was significantly higher in kidneys from CLOCK-deficient mice with ureteral obstruction. Treatment with a cyclooxygenase 2 inhibitor celecoxib significantly improved renal fibrosis in CLOCK-deficient mice. Taken together, these data establish the importance of the circadian rhythm in tubulointerstitial fibrosis and suggest CLOCK/TGF-β signaling as a novel therapeutic target of cyclooxygenase inhibition.
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Wei-Dar
authors.initials: WD
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Jih-Kai
authors.initials: JK
authors.lastname: Yeh
authors.affiliation: Department of Oncology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Meng-Ting
authors.initials: MT
authors.lastname: Peng
authors.affiliation: Department of Infectious Disease, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Shian-Sen
authors.initials: SS
authors.lastname: Shie
authors.affiliation: Renal Division, Department of Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Physiology, National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Shuei-Liong
authors.initials: SL
authors.lastname: Lin
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Tien-Hsing
authors.initials: TH
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Kuo-Chun
authors.initials: KC
authors.lastname: Hung
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Chun-Chieh
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: I-Chang
authors.initials: IC
authors.lastname: Hsieh
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Ming-Shien
authors.initials: MS
authors.lastname: Wen
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. Electronic address: cwang@ocean.ag.
authors.forename: Chao-Yung
authors.initials: CY
authors.lastname: Wang
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000172:deficiency / Q000502:physiology*; D000068579:Celecoxib / Q000627:therapeutic use; D057906:Circadian Clocks / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D007668:Kidney / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D014517:Ureteral Obstruction / Q000235:genetics / Q000503:physiopathology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D051546:Cyclooxygenase 2; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D000068579:Celecoxib