非诺贝特及二甲双胍对OLETF大鼠肾损伤和脂质沉积的影响

目的:探讨自发性2型糖尿病的动物模型OLETF大鼠在糖尿病前期时肾脂质代谢异常与早期肾病变的关系,肾脂质代谢异常的分子机制,以及非诺贝特或二甲双胍治疗对肾脂质代谢及肾病变的影响.方法:8周龄雄性OLETF大鼠,随机分为非诺贝特治疗组(OLETF/F)、二甲双胍治疗组(OLETF/M)和未治疗组,LETO大鼠为正常对照组.于17周龄及30周龄时分别杀检,测定24h尿白蛋白定量,肾皮质中甘油三酯的含量,肾皮质固醇调节元件结合蛋白-1(sterol regulatory element-binding protein 1,SREBP-1)的蛋白及mRNA表达,脂肪酸合成酶(fatty acid synthase,FAS)和乙酰辅酶A羧化酶(acetyl CoA carboxylase,ACC)的mRNA表达水平.结果:OLETF大鼠具有肥胖、高血糖、高胰岛素血症、高血脂的特点.30周龄时OLETF大鼠未治疗组与正常对照组比较,24h尿微量白蛋白显著升高,出现肾早期损伤.OLETF大鼠24 h尿白蛋白定量与肾甘油三酯含量呈正相关(r=0.870,P=0.011),随着肾甘油三酯含量加重,24 h尿白蛋白定量增多.OLETF大鼠未治疗组与正常对照组比较,调节脂肪合成的分子SREBP-1蛋白水平、FASmRNA、ACCmRNA分别升高43.2%(P＜0.01),126.0%(P＜0.01),72.3%(P＜0.01).OLETF/F组的SREBP-1蛋白水平、FASmRNA、ACCmRNA分别低于OLETF未治疗组15.7%(P=0.061),36.8%(P＜0.05),40.3%(P＜0.05).OLETF/M组的SREBP-1蛋白水平、FASmRNA、ACCmRNA分别低于OLETF未治疗组19.3%(P＜0.01),57.3%(P＜0.01),22.5%(P＜0.05).SREBP-1的mRNA水平在各组之间比较差异无统计学意义.结论:OLETF大鼠在糖尿病前期已经出现肾病变,可能与肾脂肪沉积有关.肾组织中SREBP-1水平升高,通过调节FAS,ACC等脂肪合成相关的酶,增加肾脂肪沉积,这可能是糖尿病肾病的发生机制之一.早期给予非诺贝特或二甲双胍治疗,可以减轻OLETF大鼠肾早期病变,可能通过SREBP-1及其下游脂肪合成相关酶的变化,直接改善了肾组织中的脂肪沉积.

Effect of fenofibrate and metformin on lipotoxicity in OLETF rat kidney

Objective:To explore the possible molecular mechanism of abnormal renal lipid metabolism in OLETF rats, and the effects of fenofibrate or metformin on renal local lipid metabolism. Methods: OLETF rats were randomly divided into three groups:one treated with fenofibrate, one with metformin and one without treatment. LETO rats were used as age-matched normal controls. The animals were sacrificed and the kidneys were obtained respectively at the age of 17 and 30 weeks. 24-hour urine albumin contents and TG contents in renal cortex were measured. The levels of SREBP-1 protein and mRNA in kidney were measured. FAS mRNA and ACC mRNA expressions were measured with RT-PCR. Results:OLETF rats showed characters of obesity, hyperglycemia, hyperlipidemia. At the end of thirty weeks clinical characters of renal damage appeared in OLETF rats, OLETF rats showed higher levels of 24-hour urine albumin contents than those of LETO rats. 24-hour urine albumin contents were correlated positively with TG contents in kidney. The partial correlation coefficient was 0. 870(P = 0.011) by controlling for body weight, serum lipid, blood glucose and fasting insulin concentration. OLETF rats showed higher levels of SREBP-1 protein (43. 2% , P < 0. 01 ) , FAS mRNA ( 126. 0% , P < 0. 01 ) , ACC mRNA (72. 3% , P <0.01) than those of group LETO. OLETF/F rats showed lower levels of SREBP-1 (15.7%, P =0.061), FAS mRNA (36.8%, P<0.05), ACC mRNA (40.3%, P<0.05) than those of group OLETF. OLETF/M rats showed lower levels of SREBP-1 (19. 3% , P < 0. 01) , FAS mRNA (57.3% , P<0.01) , ACC mRNA (22.5% , P<0.05) than those of group OLETF. There was no di- fference in SREBP-1 mRNA levels for each group. Conclusion:Renal damage occured in OLETF rats at the prediabetes stage. 24-hour urine albumin contents were correlated positively with TG contents in kidney. SREBP-1 might aggravate fat deposition in kidney through some enzyme associated with fat synthesis , which was a possible pathogenesis of diabetic nephropathy. Treatment with fenofibrate or metformin ameliorated renal damage in OLETF rats through SREBP-1 and some enzyme regulated by it reduced fat deposit in kidney directly.