期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 287, 期 2, 页码 G417-G424出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00294.2003
关键词
P2Y receptor; nucleoside triphosphate diphosphohydrolase; ectonucleotidase; adenosine 5 '-triphosphate receptor; fibrogenesis; cell proliferation
资金
- Canadian Institutes of Health Research [49460] Funding Source: Medline
- NIDDK NIH HHS [R01 DK058123, DK-02379, DK-34989, DK-58123, P30-DK-50306, P30 DK050306, P30 DK034989] Funding Source: Medline
Extracellular nucleotides regulate a variety of cellular activities, including proliferation of fibrogenic cells outside of the liver. However, the expression of receptors for extracellular nucleotides in hepatic stellate cells (HSC) is unknown. Thus our aims were to investigate the expression of mediators of nucleotide signaling in HSC and to determine whether extracellular nucleotides regulate HSC function. Confocal video microscopy was used to observe nucleotide-induced changes in cytosolic Ca2+ (Ca-i(2+)) in live HSC. P2Y receptor subtype expression and ectonucleotidase expression in quiescent and activated HSC were determined using RT-PCR, Northern blot, immunoblot, and confocal immunofluorescence. Functional ectonucleotidase activity was assessed using a colorimetric method. Nucleotide-sensitive procollagen-1 mRNA expression in activated HSC was assessed using real-time RT-PCR. Extracellular ATP increased Ca-i(2+) in HSC; this was inhibited by the P2 receptor inhibitor suramin. Quiescent HSC expressed the P2Y subtypes P2Y(2) and P2Y(4) and were activated by ATP and UTP, whereas activated HSC expressed the P2Y subtype P2Y(6) and were activated by UDP and ATP. Activated but not quiescent HSC expressed the ectonucleotidase nucleoside triphosphate diphosphohydrolase 2, extracellular UDP tripled procollagen-1 mRNA expression in activated HSC, and this was inhibited by the P2Y receptor inhibitor suramin. HSC express functional P2Y receptors and switch the expression of P2Y receptor subtypes on activation. Moreover, HSC differentially regulate nucleoside triphosphate diphosphohydrolase expression after activation. Because activation of P2Y receptors in activated HSC regulates procollagen-1 transcription, P2Y receptors may be an attractive target to prevent or treat liver fibrosis.
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