Objective To investigate the effects and possible mechanisms of action of celastrol in regulating renal oxidative stress in high-fat diet-induced obese mice.
Methods Twenty-four male C57BL/6 mice were equally divided into normal control group, model control group and celastrol group, with 8 mice in each group. The mice in the normal control group were fed with normal diet, while those in the model control group and celastrol group were fed with high-fat diet for 12 weeks to establish a high-fat induced obesity mouse model. Subsequently, the mice in the celastrol group were injected intraperitoneally with celastrol 100 μg/(kg·d) for 21 d. The mice in the remaining two groups were injected intraperitoneally with an equal volume of saline. Body weight, fasting blood glucose, glucose tolerance and insulin tolerance were observed in these groups. The mRNA expression levels of renal Kelch-like epichlorohydrin-associated protein 1(Keap1), nuclear factor E2-related factor 2(Nrf2) and peroxisome proliferator-activated receptor γcoactivator 1α(PGC-1α) were detected by real-time fluorescent quantitative polymerase chain reaction (RT-qPCR). The protein levels of renal Keap1, Nrf2 and PGC-1α were detected by western blot method.
Results The body weight and fasting blood glucose level of model control group were higher than that of normal control group, while were lower in the celastrol group than those of the model control group (P < 0.05). During drug intervention, the food intake of mice in the model control group was higher than that in the normal control group, while was lower in the celastrol group than that in model control group (P < 0.05). The results of glucose tolerance and insulin tolerance test showed that the blood glucose level of the model control group was higher than those of normal control group at each time point, while the blood glucose level of the celastrol group was lower than that of model control group (P < 0.05). Renal PGC-1α and Nrf2 gene expression and their protein levels were significantly lower than those of the normal control group, while Keap1 mRNA and Keap1 protein level were higher than those in the model control group(P < 0.05). The Nrf2 and PGC-1α mRNA in the kidney and expression levels of Nrf2 and PGC-1α protein of the celastrol group were higher than those of model control group, while expression levels of Keap1 mRNA and Keap1 protein of the celastrol group were lower than those of model control group (P < 0.05).
Conclusion Celastrol can improve glucose metabolism, reduce body weight and food intake in high-fat diet-induced obese mice, play anti-inflammatory and anti-oxidative stress roles, and ameliorate renal injury. Its mechanism may be related to the renal Keap1/Nrf2/PGC-1α pathway.
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