Abstract
Mice lacking A1 adenosine receptors (A1AR) were thought to be protected from developing fatty liver; however, the contribution of A1AR to hepatic fibrosis has not been explored. Here we found that the expression of A1AR was decreased in fibrotic liver induced by chronic carbon tetrachloride (CCl4) but increased in that induced by bile duct ligation (BDL). Therefore, we examined whether A1AR contributes to hepatic fibrosis in CCl4 and BDL animal models using A1AR knockout mice. Compared with wild-type (WT) mice, hepatic fibrosis resulting from chronic CCl4 exposure was attenuated in A1AR(−/−) mice with markedly decreased collagen deposition and reduced hepatic stellate cell activation, whereas bile duct-ligated A1AR(−/−) mice displayed a significant increase in hepatic fibrosis. Hepatocyte damage was reduced in A1AR(−/−) mice after a single injection of CCl4, with down-regulation of CYP2E1 and UCP2 gene expression in livers, which resulted in impaired liver sensitivity to CCl4. However, BDL caused severe bile infarcts in livers of A1AR(−/−) mice, with significantly elevated levels of bile acid compared with those in WT mice. CCl4 and BDL resulted in different expression patterns of genes involved in fibrogenesis in A1AR(−/−) mice. These results indicate that A1AR participates in the pathogenesis of hepatic fibrosis with a complex mechanism, and the effect of targeting adenosine and its receptors in the prevention of hepatic fibrosis should be cautiously evaluated.
Footnotes
This work was supported by the National Science Foundation of China [Grant 30730030]; and the Program for New Century Excellent Talents in University.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.162727.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- A1AR
- A1 adenosine receptor
- CCl4
- carbon tetrachloride
- BDL
- bile duct ligation
- UCP2
- uncoupling protein 2
- WT
- wild type
- α-SMA
- α-smooth muscle actin
- PCR
- polymerase chain reaction
- CK19
- cytokeratin 19
- HSC
- hepatic stellate cell
- TGF-β
- transforming growth factor-β
- TNF-α
- tumor necrosis factor-α
- IL
- interleukin
- PDGF
- platelet-derived growth factor
- MMP
- matrix metalloproteinase
- TIMP
- tissue inhibitor metalloproteinase
- RT
- reverse transcriptase.
- Received October 25, 2009.
- Accepted December 9, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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