大黄酸和罗格列酮对db/db糖尿病小鼠代谢紊乱和肾脏损伤的作用比较

Improvement of diabetic metabolic disorders ameliorate the renal lesion in db/db mice: comparison between rhein and rosiglitazone

目的 :比较大黄酸和罗格列酮对糖尿病db/db小鼠代谢紊乱和肾脏损伤的作用 ,探讨大黄酸防治糖尿病肾病的机制。 方法 :实验小鼠分四组 :db/m正常小鼠对照组 ;db/db糖尿病小鼠对照组 ;db/db糖尿病小鼠大黄酸 [1 2 0mg/ (Kg·d) ]治疗组 ;db/db糖尿病小鼠罗格列酮 [4mg/ (Kg·d) ]治疗组。连续灌胃 1 2周 ,于实验末比较各组体重、血糖和血脂水平。PAS染色、免疫荧光分析肾小球病理形态学改变。电镜分析线粒体数目形态改变。Real timePCR分析脂肪和肌肉组织过氧化物酶体增生物激活受体γ(PPARγ)、胰岛素抵抗因子 (resistin)和脂肪酸转运体 (FAT/CD36 )mRNA表达。 结果 :大黄酸和罗格列酮治疗均可明显降低db/db小鼠血糖水平。大黄酸治疗还可明显减轻体重 ,降低血胆固醇和三酰甘油水平 ,改善高脂血症 ;而罗格列酮治疗则增加小鼠体重 ,提高血胆固醇和低密度脂蛋白水平。组织学显示 ,db/db小鼠肾小球肥大 ,系膜区扩张 ,系膜基质增加 ,大量纤维连接蛋白 ;同时肾小管线粒体数目减少 ,体积增大 ,嵴结构不清。大黄酸和罗格列酮治疗后均可明显改善上述肾脏病理改变 ,但对线粒体的作用大黄酸较罗格列酮更为明显。db/db小鼠肌肉和脂肪组织PPARγ和resistin的表达均明显下降 ,FAT/CD36表达增加。

Objective:To test our hypothesis that reversion of insulin resistance by rhein might contribute to its therapeutic effect on diabetic nephropathy(DN) the effects of rhein and rosiglitazone on metabolic disorders and renal lesion in diabetic db/db mice were compared, and the mechanism of rhein on preventing the development of DN was also investigated Methodology:Diabetic db/db mice were continuously treated with rhein 120mg/(kg·d) or rosiglitazone 4mg/(kg·d) for 12 weeks The body weight, serum glucose and lipid were detected at the end of the study Renal histopathology was evaluated under light microscopy and immunohistochemistry staining Mitochondrial morphology was observed under electronic microscopy The expression of mRNA was determined by real time RT PCR Results:Compared with the untreated diabetic conrols, both of rhein and rosiglitazone led to similar amelioration of glomerular mesangial expansion and extracelluar matrix accumulation, as well as reduction of blood glucose level However, the diverse changers were observed in lipid metabolism after two agents treatment Rhein markedly decreased the body weight of mice [(45 0±2 60g vs (49 9±1 00g, P <0 01] and the level of plasma cholesterols [(2 1±0 20 vs (2 8±0 6 mmol/L, P <0 01], while rosiglitazone significantly increased the body weight [(52 9±2 2g vs (49 9±1 0g, P <0 01] and cholesterols [(5 5±0 6 vs (2 8±0 6 mmol/L, P <0 01] The level of low density lipoprotein (LDL was also enhanced after rosiglitazone treatment [(0 45±0 11 vs (0 13±0 04 mmol/L, P <0 01] while mild fell after rhein treatment The number of mitochondrial was decreased and the structure blurry in renal tubular epithelia from db/db mice, and which were markedly ameliorated by rhein and mildly by rosiglitazone The expression of PPARγ was down regulated in the fat and muscle of db/db mice, while up regulated after both rhein and rosiglitazone treatment The expression of resistin, a linkage between obesity and insulin resistance, was unexpectantly reduced in db/db mice and mildly decreased in fat and markedly increased in muscle after rhein or rosiglitazone treatment, confusing the role of resistin on insulin resistance The expression of fatty acid translocase (FAT/CD36) was found to be up regulated in fat and muscle of db/db mice, and attenuated by both two agents However, the effect of rhein was much more stronger than rosiglitazone Conclusion:The similar renal protective effect of rhein compared with rosiglitazone gave the evidence that reversion of insulin resistance was attributed to the prevention of DN In addition, the improvement of lipidemia by rhein might provide a better way for diabetic metabolic disorders than by rosiglitazone, which was shown an adverse consequence of hyperlipidemia and weight gain