Mindin deficiency protects the liver against ischemia/reperfusion injury.

Abstract

BACKGROUND & AIMS:

Hepatic ischemia/reperfusion (I/R) injury often occurs during liver surgery and may cause liver failure. Our previous studies revealed that Mindin is involved in the pathogenesis of ischemic stroke. However, the function of Mindin in hepatic I/R injury remains unknown.

METHODS:

Partial hepatic warm ischemia was induced in parallel in global Mindin knockout mice (Mindin KO), hepatocyte-specific Mindin knockdown mice, hepatocyte-specific Mindin transgenic mice (Mindin TG), myeloid cell-specific Mindin TG mice (LysM-Mindin TG), and their corresponding controls, followed by reperfusion. Hepatic histology, serum aminotransferase, inflammatory cytokines, and hepatocyte apoptosis and proliferation were examined to assess liver injury. The molecular mechanisms of Mindin function were explored in vivo and in vitro.

RESULTS:

Mindin KO and hepatocyte-specific Mindin knockdown mice exhibited less liver damage than controls, with smaller necrotic areas and lower serum transaminase levels. Mindin deficiency significantly suppressed inflammatory cell infiltration, cytokine and chemokine production, and hepatocyte apoptosis, but increased hepatocyte proliferation following hepatic I/R injury. In contrast, the opposite pathological and biochemical changes were observed in hepatocyte-specific Mindin TG mice, whereas no significant changes in liver damage were found in LysM-Mindin TG mice compared to non-transgenic controls. Mechanistically, Akt signaling was activated in livers of Mindin KO mice but was suppressed in Mindin TG mice. Most importantly, Akt inhibitor treatment blocked the protective effect of Mindin deficiency on hepatic I/R injury.

CONCLUSIONS:

Mindin is a novel modulator of hepatic I/R injury through regulating inflammatory responses, as well as hepatocyte apoptosis and proliferation via inactivation of the Akt signaling pathway.

• Authors: Peng Sun, Peng Zhang, Pi-Xiao Wang, Li-Hua Zhu, Yibao Du, Song Tian, Xueyong Zhu, Hongliang Li
• Journal: Journal of hepatology (J Hepatol) Vol. 63 Issue 5 Pg. 1198-211 (Nov 2015) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 26165142 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Extracellular Matrix Proteins
• mindin
• RNA

Topics

• Animals
• Apoptosis
• Blotting, Western
• Cells, Cultured
• Disease Models, Animal
• Extracellular Matrix Proteins (deficiency, genetics)
• Flow Cytometry
• Gene Expression Regulation
• In Situ Nick-End Labeling
• Liver (blood supply, metabolism, pathology)
• Liver Diseases (etiology, genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• RNA (genetics)
• Real-Time Polymerase Chain Reaction
• Reperfusion Injury (complications, genetics, metabolism)
• Signal Transduction