Sitagliptin-Dependent Differences in the Intensity of Oxidative Stress in Rat Livers Subjected to Ischemia and Reperfusion

Abstract

Purpose: Ischemia/reperfusion (IR) is the main cause of liver damage after transplantation. We evaluated the effect of sitagliptin (STG) on oxidative stress parameters in the rat liver under IR.

Methods: Rats were treated with STG (5 mg/kg) (S and SIR) or saline solution (C and CIR). Livers from CIR and SIR were subjected to ischemia (60 min) and reperfusion (24 h). During reperfusion, aminotransferases (ALT and AST) were determined in blood samples. Thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), paraoxonase-1 (PON1), glutathione peroxidase (GPx), and the mRNA expression of SOD1 were determined in liver homogenates after reperfusion. Different regions of livers were also histologically evaluated.

Results: The PON1 activity was higher, and the TBARS level was lower in SIR than in CIR. There was an inverse relationship between TBARS and PON1 levels in the whole cohort. The GPx activity was lower in ischemic than in nonischemic groups regardless of the STG treatment. In SIR, the SOD1 activity was higher compared to that in CIR. In S, the expression of SOD1 mRNA was the highest of all examined groups and positively correlated with the SOD1 activity in the whole animal cohort. During IR aminotransferases, the activity in the drug-treated group was lower in all examined points of time. In drug-treated groups, the percentage of steatosis was higher than that in nontreated groups regardless of IR.

Conclusions: The protective effect of STG on the rat liver, especially its antioxidant properties, was revealed under IR conditions.

Figure 1

Influence of IR and STG treatment on activity of ALT (a) and AST (b). Values are presented as the mean + SD. Group C, nontreated and nonsubjected to IR; group CIR, nontreated and subjected to IR; group S, STG-treated and nonsubjected to IR; group SIR, STG-treated and subjected to IR. Specific comparisons: ^∗p < 0.05 and ^∗∗p < 0.01 (compared to C), ^#p < 0.05 (compared to S), and ^ΔΔp < 0.01 (compared to CIR).

Figure 2

Influence of IR and STG treatment on TBARS (a), PON-1 (b), GPx (c), CAT (d), SOD1 (e), and mRNA for SOD1 (f) levels. Values are presented as the mean + SD. Group C, nontreated and nonsubjected to IR; group CIR, nontreated and subjected to IR; group S, STG-treated and nonsubjected to IR; group SIR, STG-treated and subjected to IR. Specific comparisons: ^∗p < 0.05 (compared to C), ^#p < 0.05 and ^##p < 0.01 (compared to S), ^Δp < 0.05 and ^ΔΔp < 0.01 (compared to CIR), and ^†p < 0.05 (compared to SIR).

Figure 3

Comparison of correlation between SOD1 expression and activity in control (nontreated) (a) and STG-treated (b) animals. Data presented as regression line with 95% confidence interval (dashed lines).

Figure 4

Histopathological examination of liver tissue. Histological examination (stained with hematoxylin-eosin, magnification ×400, bar 50 μm) from group C, rats nontreated and nonsubjected to IR (a); group CIR, rats nontreated and subjected to IR (b); group S, rats treated with STG and not subjected to IR (c); and from group SIR, rats treated with STG and subjected to IR (d). No significant differences in the hepatic structure were seen in both ischemic and nonischemic groups of rats. In drug-treated groups, the percentage of steatosis was statistically higher than that in nontreated groups (CIR vs. SIR, p < 0.05, and C vs. S, p < 0.01).