Circadian CLOCK mediates activation of transforming growth factor-β signaling and renal fibrosis through cyclooxygenase 2

Wei Dar Chen, Jih Kai Yeh, Meng Ting Peng, Shian Sen Shie, Shuei Liong Lin, Chia Hung Yang, Tien Hsing Chen, Kuo Chun Hung, Chun Chieh Wang, I. Chang Hsieh, Ming Shien Wen, Chao Yung Wang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

41 Scopus citations

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.

Original languageEnglish
Pages (from-to)3152-3163
Number of pages12
JournalAmerican Journal of Pathology
Volume185
Issue number12
DOIs
StatePublished - 12 2015

Bibliographical note

Publisher Copyright:
© 2015 American Society for Investigative Pathology.

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