MG132 Treats Obesity Related Glomerulopathy Through Upregulation Of Nrf2

Backgrounds:The growing incidence of obesity and obesity related glomerulopathy(ORG) has brought huge economic pressure on society, thus seeking a safe, effective and economic cure is the urgent problem to solve. Chronic inflammation and oxidative stress are the common pathogenesis of diabetic nephropathy and ORG, which play an important role in the occurrence and development of these diseases. Nuclear-factor-E2-related factor 2(Nrf2)-antioxidant response element(ARE) signaling pathway is a highly sensitive antioxidant defense system. In eukaryotic cells, ubiquitin proteins are degraded by ubiquitin proteasomes continuously. The proteasome inhibitor MG132, through inhibition of proteasome activity, reduces the degradation of Nrf2 and thus indirectly increases the protein expression of Nrf2. Studies have shown that by increasing the expression of Nrf2, nontoxic dose of MG132 has a good effect in alleviating the oxidative stress in kidney pathological damage processes caused by diabetes and chronic inflammation. Objective:Through this experiment,we mainly compare the effects of MG132 on the general biochemical indexes of mice, the expression of Nrf2 and its downstream proteins, inflammation and oxidative stress-associated proteins’ expression, so as to explore the role of Nrf2 mediating in MG132’s treatment of obesity related glomerulopathy. Methods:In this experiment, we randomly divided the 8 week-old C57BL/6J male mice into four groups as the following after 1 week of feeding: control group, MG132 group, obese group, obese +MG132 group. The first two groups were given a low fat diet(10% fat contained) and the latter two groups were given a high-fat diet(60% fat contained) for 12 weeks to establish a mouse model of obesity related glomerulopathy. Once the models were successfully established, we started to give the mice in MG132 group and obese +MG132 group MG132(20μg/Kg/, every other day); however, the age-matched control mice were given equal dose of normal saline by intraperitoneal injection. After 8 weeks of treatment, mice were sacrificed to collect the corresponding specimens. Then we used Western blot method and some related kits for detection of changes in renal function and other biochemistry indexes. Results:These results suggest that compared with control group, body weight, kidney wet weight, epididymal fat wet weight, triglyceride and urinary protein excretion in obese mice are significantly increased; small dose of MG132 significantly decrease these indicators, although triglyceride is not significantly reduced, it shows a downward trend. In addition, indexes representing oxidative stress and inflammatory damage in obesity group are much higher, while the protein expression level of Nrf2 and its downstream antioxidant reductase protein are lower than those in the compare group; when given MG132, indexes representing oxidative stress and inflammatory damage in obesity+MG132 mice were markedly alleviated, accompanied by increase of Nrf2 and its downstream antioxidant reductase protein expression level in renal tissue.Conclusion:MG132 can reduce renal inflammation and oxidative damage of ORG mice, and its mechanism may be related to the upregulation of Nrf2 signaling pathway.