脂联素受体介导小檗碱减轻糖尿病肾病肾脏脂毒性

Adiponectin receptor mediated berberine to alleviate renal lipid toxicity in mice with diabetic kidney disease

目的探讨脂联素受体1/2(adiponectin receptor 1/2,AdipoR1/R2)介导小檗碱减轻糖尿病肾病肾脏脂毒性的作用。方法选择C57BLKS/J db/db小鼠,以db/m小鼠为对照,分为4组,每组8只,分别给予小檗碱(150 mg·kg^(﹣1)·d^(﹣1))或安慰剂灌胃,连续12周。干预结束后测定血糖、血脂、尿微量白蛋白/肌酐比值、尿白蛋白排泄率;取肾脏组织进行病理形态学检查,通过油红O染色、免疫组化、ELISA和Western印迹测定肾脏脂质沉积、AdipoR1/R2表达、转化生长因子β1(TGF-β1)及Ⅳ型胶原(Col-Ⅳ)表达等。用人肾小球内皮细胞系(HGEC)验证AdipoR1/R2介导小檗碱减轻肾脏脂毒性的作用。结果小檗碱干预后,db/db小鼠体质量减轻,血糖、血脂、蛋白尿减少(P<0.05),肾脏脂质沉积、病理改变减轻;db/db小鼠肾脏组织AdipoR1/R2表达上调,TGF-β1、Col-Ⅳ表达下调,PPAR-α、p-AMPK表达上调(P<0.05)。db/db小鼠血清干预后,高脂培养的HGEC细胞中TGF-β1、Col-Ⅳ表达下调,PPAR-α、p-AMPK表达上调(P<0.05);沉默HGEC细胞上的AdipoR1/R2后,TGF-β1、Col-Ⅳ表达上调,PPAR-α及p-AMPK表达下调(P<0.05)。结论小檗碱可以减轻糖尿病肾病小鼠模型的肾脏脂毒性,该作用可能由脂联素受体介导。

Objective To explore whether adiponectin receptor 1/2(AdipoR1/R2)mediates berberine to alleviate renal lipid toxicity in mice with diabetic kidney disease.Methods C57BLKS/J db/db mice and db/m mice were selected and divided into 4 groups,with 8 in each group.db/db mice and db/m mice were given berberine(150 mg·kg^(﹣1)·d^(﹣1))or placebo by gavage for 12 weeks,respectively.After intervention,blood glucose,blood lipids,urinary microalbumin/creatinine ratio and urinary albumin excretion rate were determined.Kidney tissues were taken for pathological examination,and oil red O staining,immunohistochemistry,ELISA and Western blotting were used to examine lipid deposition,AdipoR1/R2 expression and fibrosis markers expressions,etc.,respectively.The human glomerular endothelial cell line(HGEC)was used to verify the role of AdipoR1/R2 in berberine alleviating renal lipid toxicity.Results After berberine intervention,the body weight,blood glucose,lipids,proteinuria,renal lipid deposition,and renal pathological changes decreased in db/db mice(P<0.05);the expressions of AdipoR1 and AdipoR2 increased,expressions of TGF-β1 and Col-Ⅳdecreased,and the expressions of PPAR-αand p-AMPK increased in kidney tissue of db/db mice(P<0.05).In high-fat cultured HGEC cells treated with berberine-treated db/db mouse serum,the expressions of TGF-β1 and Col-Ⅳdecreased,while the expressions of PPAR-αand p-AMPK increased(P<0.05);after AdipoR1/R2 on HGEC cells were silenced,the expressions of TGF-β1 and Col-Ⅳincreased,while the expressions of PPAR-αand p-AMPK decreased(P<0.05).Conclusions Berberine can reduce renal lipid toxicity in diabetic nephropathy mice,and adiponectin receptor may mediate this effect of berberine.