Down-regulation of miR-192-5p protects from oxidative stress-induced acute liver injury

Abstract

miR-192-5p has gained increasing relevance in various diseases, however, its function in acute liver injury is currently unknown. We analysed miR-192-5p serum levels and hepatic miR-192-5p expression in mice after hepatic ischaemia and reperfusion (I/R) as well as in toxic liver injury. On a functional level, miRNA levels were analysed in the different hepatic cell-compartments and in the context of tumour necrosis factor (TNF)-dependent liver cell death. We detected increased serum levels of miR-192-5p after hepatic I/R- and carbon tetrachloride (CCl4)-induced liver injury. miR-192-5p levels correlated with the degree of liver damage and the presence of hepatic cell death detected by TUNEL stainings (terminal deoxynucleotidyltransferase-mediated dUTP biotin nick-end labelling stainings). Moreover, expression of miR-192-5p was increased in a hypoxia/reoxygenation (H/R) model of in vitro hepatocyte injury, supporting that the passive release of miR-192-5p represents a surrogate for hepatocyte death in liver injury. In critically ill patients, miR-192-5p levels were elevated selectively in patients with liver injury and closely correlated with the presence of hepatic injury. In contrast with up-regulated miR-192-5p in the serum, we detected a down-regulation of miR-192-5p in both injured mouse and human livers. Deregulation of miR-192-5p in livers was dependent on stimulation with TNF. Functional experiments confirmed a protective effect of down-regulation of miR-192-5p in hepatocytes, suggesting a role of miR-192-5p in limiting liver injury. Finally, we identified Zeb2, an important regulator of cell death, as a potential target gene mediating the function of miR-192-5p Our data suggest that miR-192-5p is involved in the regulation of liver cell death during acute liver injury and might represent a potent marker of hepatic injury.

Characteristic MicroRNA Expression Induced by δ-Opioid Receptor Activation in the Rat Liver Under Prolonged Hypoxia

“…Yang et al reported that miR-107-3p inhibition is able to protect the rat cerebrum from excitatory neurotoxicity during ischemia-reperfusion injury by targeting GLT1 [66, 67]. Roy et al reported that miR-192-5p inhibition protects from oxidative stress-induced acute liver injury by targeting Zeb2 and might represent a potent marker of hepatic injury [13]. Based on these early studies and our new observations, we are confident that DOR signaling is able to increase hepatic tolerance to hypoxic stress by increasing the activities of miR-107-3p and miR-192-5p.…”

“…Moreover, miR-146a could ameliorate liver hypoxia/reoxygenation injury in vitro by directly suppressing IRAK1 and TRAF6 [12] and miR-494 was protective against hypoxia-induced apoptosis in liver through HIF-1α upregulation by activating PI3K/ Akt pathway [14]. In addition, there is accumulating evidence suggesting that many other miRNAs are involved in liver reactions to hypoxic stress, such as miR-150 downregulation under hypoxia by targeting VEGF-A and HIF1α during liver regeneration [16, 57], miR-192-5p upregulation in hepatocyte injury [13] and increased miR-462/731 cluster in the hypoxia-exposed liver of Megalobrama amblycephala [58] and zebrafish [59]. …”

“…It has been widely reported that miRNA activity participates in the control of a wide range of biological functions and processes such as hypoxic/ischemic response, tumorigenesis, cell differentiation, and immune regulation [9-11]. For example, miR-146a attenuates hypoxia/reoxygenation injury in vitro by directly suppressing IRAK1 and TRAF6 in liver [12] and miR-192-5p protects liver cell from hepatic injury induced by oxidative stress by targeting Zeb2 [13]. Also, miR-494 protects against hypoxia-induced apoptosis by upregulating HIF1α expression through activating PI3K/Akt pathway [14].…”

MicroRNAs in injury and repair

“…In addition, miR-192 and miR-122 were effective serum biomarkers of liver injury in rats that experienced acute liver transplantation rejection[45]. In a recent study, miR-192 was increased in the sera of humans with acute liver failure and in mice subjected to hepatic ischemia-reperfusion injury or liver injury induced by CCl4[46]. In addition, miR-192 in sera was correlated with increasing liver damage.…”

“…However, miR-192 was downregulated in liver tissues of mice and humans with liver injury. In a mouse hepatoma cell line, miR-192 was shown to target Zeb2, an anti-apoptotic gene, and increased susceptibility to oxidative stress[46]. …”