Liraglutide improves renal oxidative stress in rats with insulin resistance

Objective To investigate the effects of liraglutide on renal function, the glomerular morphology in electron microscope and oxidase subunit of dihydronicotinamide adenine dinuclectide phosphate(NADPH) —P22phox and P47phox in kidney in rats with insulin resistance(IR). Methods Fifty-four male Wistar rats were divided into normal diet group(group A, n=16) and high-fat diet group(n= 38). Hyperinsulinemic-euglycemic clamp test was performed at the waking state after 8 weeks feeding. Glucose infusion rate(GIR) was measured to determine if IR rats model was successful. The rats with high-fat diet were randomly divided into three groups: high-fat diet group(group B, n=11), liraglutide 100 μg/(kg·d) group (group C, n=11), liraglutide 200 μg/(kg·d) group(group D, n=11). The rats with normal diet was group A(n=11). Daily subcutaneous injections of saline were given group A, B, while liraglutide intervention was given in group C,D. After 2 weeks, biochemical markers were measured in each group. Realtime Quantitative PCR and Western blotting were used for detecting the expression of P22phox and P47phox in kidney. Renal ultrastructure was observed by transmission electron microscope. LSD t test was performed in comparison between the two groups, while one way variance analysis for multiple groups comparison. Results (1) Compared with group A, the expression of P22phox and P47phoxin were significantly increased in group B (P22phox mRNA: 4.9±0.4 vs 1.0±0, P22phox protein: 2.72±0.20 vs 1.27±0.24; P47phox mRNA:4.8±0.8 vs 1.0 ± 0, P47phox protein: 2.17 ± 0.39 vs 1.13 ± 0.15, t=4.225-16.041, all P<0.05). (2) Compared with the group B, the expression level of P22phox and P47phox were decreased in liraglutide groups (P22phox mRNA: 2.3 ± 0.4, 4.5 ± 0.4, 4.9 ± 0.4 in group D,C,B, respectively; P22phox protein 1.75 ± 0.13, 2.32 ± 0.21, 2.72 ± 0.20; P47phox mRNA: 2.2 ± 0.3, 3.6 ± 0.4, 4.8 ± 0.8, in group D, C, B, respectively; P47phox protein: 1.30±0.18, 1.66±0.15, 2.17±0.39), and group D decreased more significantly than group C (t=6.482, 3.401, 4.875, 2.067, all P<0.05). (3) The basement membrane of glomerular in group B was uneven thickness, with part of the podocytes swelling, or even disappear. It was improved after the intervention of liraglutide, especially in group D. Conclusion Reducing oxidative stress by inhibiting the expression of P22phox, P47phox in kidney, maybe one of the kidney protection mechanisms of liraglutide on IR rats. Key words: Liraglutide; Insulin resistance; Oxidative stress; NADPH oxidase; Kidney