Protein kinase C-β inhibitor treatment attenuates hepatic ischemia and reperfusion injury in diabetic rats

Abstract

Abstract. Hepatic ischemia and reperfusion (I/R) injury plays an active role in hepatic resection and transplantation. While the effects of protein kinase C (PKC)-βII activation and the role of PKC-β inhibitors are well understood in myocardial I/R in diabetes, they remain unclear in liver I/R. The aim of this study was to explore the effect of PKC-β inhibition and the potential mechanism by which PKC-β inhibitor treatment protects against hepatic I/R injury in diabetic rats. Diabetic rats were established and randomized into two groups. These were an untreated group (n=10), which did not receive any treatment, and a treatment group (n=10), orally treated with ruboxistaurin at a dose of 5 mg/kg/day for 2 weeks. The rats from the two groups were subjected to hepatic I/R. Aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels were measured by enzymatic methods at 1, 3 and 5 h after I/R. Tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule 1 (ICAM-1) were examined by enzyme-linked immunosorbent assay at the same time-points. Nuclear factor-κB (NF-κB) p65 expression was analyzed by immunofluorescence and western blotting. Apoptosis of hepatic cells was examined by the western blot analysis of caspase 3 expression and by DNA ladder analysis. Pathological changes were examined using light and electron microscopy. Serum AST and LDH levels in the PKC-β inhibitor treatment group were diminished compared with those in the untreated group (P<0.01). Serum TNF-α and ICAM-1 (P<0.01) levels were also decreased at different time-points in the PKC-β inhibitor treatment group. The relative expression of NF-κB p65 and caspase 3 in the hepatic tissue was weakened in the PKC-β inhibitor treatment group compared with that in the untreated group (P<0.01). Pathological changes in hepatic tissue were attenuated by the PKC-β inhibitor. In conclusion, PKC-β inhibitor treatment protected against liver I/R injury in diabetic rats. The mechanisms probably involved the attenuation of microvascular injury, reduced transport of injury-associated factors and diminishment of the activation of NF-κB p65.

Sevoflurane relieves hepatic ischemia–reperfusion injury by inhibiting the expression of Grp78

“…Hepatic ischemia–reperfusion injury has serious adverse effect on patients prognosis [ 17 ]. Some studies have shown that cytokines are involved in the entire pathophysiological process of hepatic ischemia–reperfusion injury through aggravating inflammatory reactions and cell damage [ 18–20 ].…”

Glycine Protects H9C2 Cardiomyocytes from High Glucose- and Hypoxia/Reoxygenation-Induced Injury via Inhibiting PKCβ2 Activation and Improving Mitochondrial Quality

“…Downregulation of PKC β 1/2 and upregulation of penumbra proteins involved in mitochondria quality control and mitophagy could be associated with tissue recovery and alleviation in penumbra around a photothrombotic infarction core in rat cerebral cortex [ 34 ]. Besides, selective inhibition of PKC β 2 has been identified to ameliorate myocardial [ 35 ] and hepatic [ 36 ] IRI in diabetes via decreasing ROS production. Given the cytoprotection of mitophagy in IRI [ 37 ], it is reasonable that PKC β 2 participated in mitophagic regulation during diabetic myocardial IRI.…”

Cellular death, reactive oxygen species (ROS) and diabetic complications

“…Maleimide Derivative 3 is a compound similar to Ruboxistaurin with the highest of binding affinities and this might also be used in the treatment of diabetic retinopathy 47 . A diabetic rat that was treated with the PKC-βII inhibitor showed diminished expressions of TNF-α, ICAM-1 (Intercellular Adhesion Molecule 1), NFk-B-Bp65, and Caspase 3, besides protecting hepatic ischemia and reperfusion 48 .…”