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LIVER AND BILIARY TRACT

Expression of P2Y nucleotide receptors and ectonucleotidases in quiescent and activated rat hepatic stellate cells

¹Yale University School of Medicine and Yale Liver Center, New Haven, Connecticut 06520; ²Harvard Medical School, Boston, Massachusetts 02215; ³University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; and ⁴Centre de récherche en Rhumatologie et Immunologie, Université Laval, Sainte-Foy, Quebec, Canada G1V 4G2

Submitted 14 July 2003 ; accepted in final form 14 January 2004

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_i²⁺) 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_i²⁺ in HSC; this was inhibited by the P2 receptor inhibitor suramin. Quiescent HSC expressed the P2Y subtypes P2Y₂ and P2Y₄ and were activated by ATP and UTP, whereas activated HSC expressed the P2Y subtype P2Y₆ 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.

P2Y receptor; nucleoside triphosphate diphosphohydrolase; ectonucleotidase; adenosine 5'-triphosphate receptor; fibrogenesis; cell proliferation

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