Circadian CLOCK Mediates Activation of Transforming Growth Factor-β Signaling and Renal Fibrosis through Cyclooxygenase 2

被引：48

作者：

Chen, Wei-Dar ^{[1
]}

Yeh, Jih-Kai ^{[1
]}

Peng, Meng-Ting ^{[2
]}

Shie, Shian-Sen ^{[3
]}

Lin, Shuei-Liong ^{[4
,5
]}

Yang, Chia-Hung ^{[1
]}

Chen, Tien-Hsing ^{[1
]}

Hung, Kuo-Chun ^{[1
]}

Wang, Chun-Chieh ^{[1
]}

Hsieh, I-Chang ^{[1
]}

Wen, Ming-Shien ^{[1
]}

Wang, Chao-Yung ^{[1
]}

机构：

[1] Chang Gung Univ, Coll Med, Chang Gung Mem Hosp, Dept Cardiol, Taoyuan 333, Taiwan

[2] Chang Gung Univ, Coll Med, Chang Gung Mem Hosp, Dept Oncol, Taoyuan 333, Taiwan

[3] Chang Gung Univ, Coll Med, Chang Gung Mem Hosp, Dept Infect Dis, Taoyuan 333, Taiwan

[4] Natl Taiwan Univ Hosp, Dept Med, Div Renal, Taipei, Taiwan

[5] Natl Taiwan Univ, Coll Med, Taipei 10764, Taiwan

来源：

AMERICAN JOURNAL OF PATHOLOGY | 2015年 / 185卷 / 12期

关键词：

UNILATERAL URETERAL OBSTRUCTION; NIGHT-SHIFT WORK; TUBULOINTERSTITIAL FIBROSIS; GENE PER2; TGF-BETA; IN-VIVO; EXPRESSION; KIDNEY; MAMMALS; MICE;

D O I：

10.1016/j.ajpath.2015.08.003

中图分类号：

R36 [病理学];

学科分类号：

100104 ;

摘要：

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-beta (TGF-beta) expression. TGF-beta 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-beta signaling as a novel therapeutic target of cyclooxygenase inhibition.

引用

页码：3152 / 3163

页数：12

共 59 条

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