Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 15;39(13):e70775.
doi: 10.1096/fj.202500010RR.

NTPDase8 Protects Against Liver Ischemia-Reperfusion Injury in Mice

Taha Kelestemur  1 , Simon C Robson  2 , Zoltán H Németh  1   3 , Pal Pacher  4 , Muhammed Arif  4 , Mehmet S Aydin  5 , Baris E Suzek  6 , Julie Pelletier  7 , Keri E Lunsford  8 , Robert F Schwabe  9 , Yana Geng  9 , Jean Sévigny  7   10 , György Haskó  1
Affiliations

NTPDase8 Protects Against Liver Ischemia-Reperfusion Injury in Mice

Taha Kelestemur et al. FASEB J. .

Abstract

CD39 or NTPDase1 and other nucleoside triphosphate diphosphohydrolases (NTPDases), including NTPDase2, NTPDase3, and NTPDase8, regulate purinergic signaling through tuning the extracellular levels of purine nucleotides and nucleosides. Purinergic signaling regulates liver ischemia-reperfusion (I/R) injury, and CD39 is protective. However, the role of other NTPDases is unknown. In this study, we investigated the role of NTPDase2, NTPDase3, and NTPDase8. Global Entpd2-/-, Entpd3-/-, and Entpd8-/- and control wild type (WT) mice were subjected to liver I/R. In addition, WT and Entpd8-/- mice underwent global ischemia induced by hemorrhagic shock and resuscitation and injury evaluated. Bone marrow chimeric mice were generated to understand the role of NTPDase expression on hematopoietic cells in regulating liver injury. Although WT, Entpd2-/- and Entpd3-/- mice exhibited comparable levels of liver injury following local IR, Entpd8-/- mice had increased liver injury compared to WT mice. Studies with bone marrow chimeric mice indicated that NTPDase8 on parenchymal liver cells protected against hepatic injury. This was confirmed by single-nucleus RNAseq showing hepatocytes are the dominant cell type expressing NTPDase8 in the liver. Entpd8-/- mice after I/R injury were noted to have higher ATP concentrations in the liver and plasma. The P2 receptor antagonist suramin decreased liver injury in Entpd8-/- mice indicating P2 signaling contributes to liver injury in these mice. Finally, Entpd8-/- mice had increased liver injury compared to WT mice also after hemorrhagic shock and resuscitation. These findings highlight the differential roles of NTPDase family members in the liver, with parenchymal/hepatocyte expression of NTPDase8 emerging as a critical suppressor of the inflammatory and metabolic responses to hepatic I/R insult, even in the presence of vascular NTPDase1 expression.

Keywords: NTPDase2; NTPDase3; NTPDase8; NTPDases; acute liver injury.

PubMed Disclaimer

References

    1. K. B. Walsh, A. H. Toledo, F. A. Rivera‐Chavez, F. Lopez‐Neblina, and L. H. Toledo‐Pereyra, “Inflammatory Mediators of Liver Ischemia‐Reperfusion Injury,” Experimental and Clinical Transplantation 7, no. 2 (2009): 78–93.
    1. P. Pacher and G. Hasko, “Endocannabinoids and Cannabinoid Receptors in Ischaemia‐Reperfusion Injury and Preconditioning,” British Journal of Pharmacology 153, no. 2 (2008): 252–262.
    1. Z. Cao, M. M. Mulvihill, P. Mukhopadhyay, et al., “Monoacylglycerol Lipase Controls Endocannabinoid and Eicosanoid Signaling and Hepatic Injury in Mice,” Gastroenterology 144, no. 4 (2013): 808–817.
    1. X. Sun, M. Imai, M. Nowak‐Machen, et al., “Liver Damage and Systemic Inflammatory Responses Are Exacerbated by the Genetic Deletion of CD39 in Total Hepatic Ischemia,” Purinergic Signal 7, no. 4 (2011): 427–434.
    1. A. L. Giuliani, A. C. Sarti, and F. Di Virgilio, “Extracellular Nucleotides and Nucleosides as Signalling Molecules,” Immunology Letters 205 (2019): 16–24.

LinkOut - more resources