| Background & AimDiabetic nephropathy (DN) is one of the important microvascular complications of diabetes mellitus with a significant increase in morbidity and mortality in patients with diabetes, which has become a major threat of people’s health. The pathogenesis of DN is complicated and not very clear, and there is no drug that can specificately treat DN. It is necessary to identify new strategies that could specifically target on DN.Except metabolism factors,recent studies have shown that inflammation play critical roles in promoting the development and progression of DN. Macrophages are key inflammatory cells mediating kidney inflammation. It has been found that macrophages accumulation is substantially increased in kidney tissue and associated with the progression of renal injury and a decline in renal function in experimental and human diabetes.On being activated, macrophages will secrete many inflammation factors, which will play an important role in the development of renal fibrosis.The over-activation of Renin Angiotensin system, especially by producing more angiotensin Ⅱ (AngⅡ) is an important link between inflammation and DN. Possible mechanism is the decrease of angiotesionl-7(Ang 1-7) and the increase of Ang II. An increasing number of evidence indicated that Ang 1-7 exerted anti-inflammation in many diseases. AVE0991, a non-peptide Mas-receptor agonist has been reported to mimic the action of Ang 1-7 in many tissues by its vasodilating and natriuretic properties. Moreover AVE0991 has a longer biological half-life and is more stable than Ang 1-7.Based on the backgrounds mentioned above,we explore the effect of AVE0991 on inflammation factors secreted by macrophages and fibrosis in streptozotocin-induced diabetic rats.MethodsHere, we used STZ-induced Wister as the research objects. Rats were randomly divided into three groups:normal control group (NC group, n=10), diabetic nephropathy group (DN group, n=10) and AVE0991 treat diabetic nephropathy group (AVE0991 group, n=10). At the end of the 8th week after the construction of the model, the latter two group of rats received treatment with vehicle or AVE0991 by gavage for four continuous weeks. Then specimens were collected. Biochemical indicators were detected. Renal pathological changes in mice were observed by Periodic Acid Schiff (PAS) staining. CollagenI,FN expression in the kidney tissues were detected by immunohistochemistry. The mRNA and protein levels of IL-1β, IL-6. TNF-a were determined by real-time PCR. IL-1β, IL-6. TNF-a level were determined by ELISA.Western blot method was used to detect the expressions of TGF-β.SPSS 16.0 software was used for statistical analysis.Results1. Biochemical indicators and kidney pathological results proved that the rat suffered from diabetic kidney damages in the DN group. Compared with the DN group,AVE group exhibited lower 24h-urine protein excretion and serum creatinine.2. The results of immunohistochemistry indicated significant increase in the DN group comparing NC group in the level of CollagenI, FN.While AVE0991 group significant decreased compared with DN group (P<0.05)3. The detection results of the real time PCR and ELISA showed that comparing with the NC group, the mRNA and protein levels of IL-1β, IL-6, TNF-a were reduced in the kidneys of the DN group (P<0.05).AVE group’s mRNA and protein levels of IL-1β, IL-6, TNF-α is significant decreased compared with DN group (P<0.05).4. The results of TGF-β detected by western blot showed that comparing with the NC group, TGF-β were increased in the kidneys of the DN group (P<0.05).AVE group had a decreased expression of TGF-β compared with DN group. TGF-β compared with DN group (P＜0.05)ConclusionsAVE0991 may have therapeutic potential in improving diabetic renal function by reducing inflammation level and renal fibrosis. |
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