Circadian CLOCK Mediates Activation of Transforming Growth Factor-ß Signaling and Renal Fibrosis through Cyclooxygenase 2.
Am J Pathol
; 185(12): 3152-63, 2015 Dec.
Article
em En
| MEDLINE
| ID: mdl-26458764
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-ß (TGF-ß) expression. TGF-ß 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-ß signaling as a novel therapeutic target of cyclooxygenase inhibition.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Transformador beta
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Ciclo-Oxigenase 2
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Proteínas CLOCK
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Relógios Circadianos
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Rim
Limite:
Animals
Idioma:
En
Revista:
Am J Pathol
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Taiwan