Ecto-Nucleotide Triphosphate Diphosphohydrolase-2 (NTPDase2) Deletion Increases Acetaminophen-Induced Hepatotoxicity

International Journal of Molecular Sciences

Anna Riddermann¹  Linda Feldbrügge¹  Felix Krenzien¹  Katrin Splith¹  Johann Pratschke¹  Sandra Richter¹  Moritz Schmelzle¹  SantiagoAndres Ortiz Galindo¹  Eva Csizmadia²  SimonC. Robson²  Tobias Müller³  Ines Kämmerer⁴ 

[1] Department of Surgery, Campus Charité Mitte and Campus Virchow Klinikum, Charité—Universitätsmedizin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany;Departments of Medicine and Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA 02215, USA;Division of Hepatology and Gastroenterology, Medical Department, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany;Translational Centre for Regenerative Medicine (TRM), Universität Leipzig, 04103 Leipzig, Germany;

关键词: Entpd2;    NTPDase2;    purinergic signaling;    APAP hepatotoxicity;   

DOI  :  10.3390/ijms21175998

来源: DOAJ

【 摘 要 】

Ecto-nucleotidase triphosphate diphosphohydrolase-2 (NTPDase2) is an ecto-enzyme that is expressed on portal fibroblasts in the liver that modulates P2 receptor signaling by regulating local concentrations of extracellular ATP and ADP. NTPDase2 has protective properties in liver fibrosis and may impact bile duct epithelial turnover. Here, we study the role of NTPDase2 in acute liver injury using an experimental model of acetaminophen (APAP) intoxication in mice with global deletion of NTPDase2. Acute liver toxicity was caused by administration of acetaminophen in wild type (WT) and NTPDase2-deficient (Entpd2 null) mice. The extent of liver injury was compared by histology and serum alanine transaminase (ALT). Markers of inflammation, regeneration and fibrosis were determined by qPCR). We found that Entpd2 expression is significantly upregulated after acetaminophen-induced hepatotoxicity. Entpd2 null mice showed significantly more necrosis and higher serum ALT compared to WT. Hepatic expression of IL-6 and PDGF-B are higher in Entpd2 null mice. Our data suggest inducible and protective roles of portal fibroblast-expressed NTPDase2 in acute necrotizing liver injury. Further studies should investigate the relevance of these purinergic pathways in hepatic periportal and sinusoidal biology as such advances in understanding might provide possible therapeutic targets.

【 授权许可】

Unknown