Abstract:
Diabetes-related vascular complications include diabetic cardiovascular diseases (CVD), diabetic nephropathy (DN) and diabetic retinopathy, etc. DN can promote the process of end-stage renal disease. On the other hand, atherosclerosis accelerates kidney damage. It is really an urge to explore the mechanisms of diabetes-exacerbated atherosclerosis as well as new agents for treatment of diabetes-exacerbated atherosclerosis and the complications. In this study we investigated the therapeutic effects of fisetin, a natural flavonoid from fruits and vegetables, on kidney injury caused by streptozotocin (STZ)-induced diabetic atherosclerosis in low density lipoprotein receptor deficient (LDLR-/-) mice. Diabetes was induced in LDLR-/- mice by injecting STZ, and the mice were fed high-fat diet (HFD) containing fisetin for 12 weeks. We found that fisetin treatment effectively attenuated diabetes-exacerbated atherosclerosis. Furthermore, we showed that fisetin treatment significantly ameliorated atherosclerosis-enhanced diabetic kidney injury, evidenced by regulating uric acid, urea and creatinine levels in urine and serum, and ameliorating morphological damages and fibrosis in the kidney. In addition, we found that the improvement of glomerular function by fisetin was mediated by reducing the production of reactive oxygen species (ROS), advanced glycosylation end products (AGEs) and inflammatory cytokines. Furthermore, fisetin treatment reduced accumulation of extracellular matrix (ECM) in the kidney by inhibiting the expression of vascular endothelial growth factor A (VEGFA), fibronectin and collagens, while enhancing matrix metalloproteinases 2 (MMP2) and MMP9, which was mainly mediated by inactivating transforming growth factor β (TGFβ)/SMAD family member 2/3 (Smad2/3) pathways. In both in vivo and in vitro experiments, we demonstrated that the therapeutic effects of fisetin on kidney fibrosis resulted from inhibiting CD36 expression. In conclusion, our results suggest that fisetin is a promising natural agent for the treatment of renal injury caused by diabetes and atherosclerosis. We reveal that fisetin is an inhibitor of CD36 for reducing the progression of kidney fibrosis, and fisetin-regulated CD36 may be a therapeutic target for the treatment of renal fibrosis.
摘要:
糖尿病相关血管并发症包括糖尿病心血管疾病(CVD),糖尿病肾病(DN)和糖尿病视网膜病变,等。DN可促进终末期肾病的进程。另一方面,动脉粥样硬化加速肾脏损害。探索糖尿病加剧的动脉粥样硬化的机制以及治疗糖尿病加剧的动脉粥样硬化和并发症的新药确实是一种迫切需要。在这项研究中,我们调查了非塞素的治疗效果,一种来自水果和蔬菜的天然类黄酮,在低密度脂蛋白受体缺陷(LDLR-/-)小鼠中,链脲佐菌素(STZ)诱导的糖尿病动脉粥样硬化引起的肾损伤。通过注射STZ在LDLR-/-小鼠中诱导糖尿病,给小鼠喂食含有非瑟酮的高脂饮食(HFD)12周。我们发现非塞素治疗可有效减轻糖尿病加剧的动脉粥样硬化。此外,我们表明,非塞素治疗可显着改善动脉粥样硬化增强的糖尿病肾损伤,通过调节尿酸来证明,尿液和血清中的尿素和肌酐水平,并改善肾脏的形态损伤和纤维化。此外,我们发现非塞素对肾小球功能的改善是通过减少活性氧(ROS)的产生来介导的,高级糖基化终产物(AGEs)和炎性细胞因子。此外,非塞素治疗通过抑制血管内皮生长因子A(VEGFA)的表达减少了肾脏细胞外基质(ECM)的积累,纤连蛋白和胶原蛋白,同时增强基质金属蛋白酶2(MMP2)和MMP9,这主要是通过失活转化生长因子β(TGFβ)/SMAD家族成员2/3(Smad2/3)途径介导的。在体内和体外实验中,我们证明了非塞素对肾纤维化的治疗作用是由于抑制CD36的表达。总之,我们的研究结果表明,非塞素是治疗糖尿病和动脉粥样硬化引起的肾损伤的有前途的天然药物。我们发现,非塞素是CD36的抑制剂,用于减少肾脏纤维化的进展,和非塞素调节的CD36可能是治疗肾纤维化的治疗靶标。