中国临床药学杂志

目的探讨全反式维甲酸(atRA)对糖尿病大鼠肾脏组织骨形成蛋白-7(BMP7)、转化生长因子-β1(TGFβ1)表达和细胞外基质(ECM)Ⅳ、Ⅲ型胶原代谢的影响。方法随机选择24只♂SD大鼠制作糖尿病模型,其中12只入糖尿病模型(DM)组,另12只入糖尿病模型+atRA(DM+atRA)组,此外再随机选择12只正常大鼠作为空白对照(NC)组。分别于第8、12周末各组处死6只大鼠,通过光镜、电镜观察各组大鼠肾脏病理结果;通过免疫组织化学方法观察BMP7,TGFβ1,Ⅳ、Ⅲ型胶原表达,并进行半定量分析;通过实时荧光定量PCR方法对TGFβ1mRNA、BMP7mRNA进行相对定量分析。结果 DM+atRA组大鼠肾组织BMP7表达较同时期DM组增加(P<0.01),主要表达于大鼠肾小管上皮细胞,而TGFβ1表达较同时期DM组减少(P<0.01);且DM+atRA组大鼠肾组织ECM重要成分Ⅳ、Ⅲ型胶原表达与DM组相比较显著减少(P<0.01)。同时观察到BMP7蛋白与Ⅳ型胶原蛋白表达呈负相关(r=-0.75,P<0.01),与Ⅲ型胶原蛋白表达呈负相关(r=-0.71,P<0.01),与TGFβ1蛋白表达呈负相关(r=-0.86,P<0.01)。荧光定量PCR结果表明,DM+atRA组BMP7mRNA水平升高,TGFβ1mRNA水平下降,且两者呈显著负相关(r=-0.83,P<0.01)。结论 atRA能减轻糖尿病大鼠肾脏病理损伤,延缓肾脏纤维化,这一防治作用可能与其增加BMP7表达,下调TGFβ1表达从而减少肾组织ECM沉积有关。

AIM To explore the effects of all-trans retinoic acid(atRA) on the expression of bone morphogenetic protein-7(BMP-7),transforming growth factor-β1(TGF-β1) and the metabolism of collagen Ⅳ,collagen Ⅲ in kidney tissues of streptozotocin(STZ)-induced diabetic rats.METHODS Rats injected with STZ were randomly divided into model group(DM)and therapy group(DM+atRA).Other 12 normal rats were used as control group(NC).The treatment was lasted for 8 weeks or 12 weeks,and renal pathological change was evaluated by light and electron microscopy.The expression of BMP-7,TGF-β1 and collagen Ⅳ,collagen Ⅲ in kidney tissues were tested by immunohistochemistry technique.The mRNA expression of BMP-7 and TGF-β1 in kidney tissues was quantitatively determined through real time reverse transcription polymerase chain reaction(real time RT-PCR).RESULTS The expression of BMP-7 in kidney in DM+atRA group was significantly higher than that in DM group(P<0.01),but the expression of TGF-β1,collagen Ⅲ and Ⅳ of kidney in DM+atRA group was significantly lower than that in DM group(P<0.01).And the levels of protein exprssion of BMP-7 were negatively correlated with the levels of TGF-β1(r=-0.86,P<0.01),collagen Ⅳ(r=-0.75,P<0.01)and collagen Ⅲ(r=-0.71,P<0.01),respectively.The levels of mRNA exprssion of BMP-7 in kidney in DM+atRA group were higher than those in DM group(P<0.01),but the levels of TGF-β1 lower than those in DM group(P<0.01).Also the levels of mRNA exprssion of BMP-7 were negatively correlated with the levels of TGF-β1(r=-0.83,P<0.01).CONCLUSION The atRA can relieve renal injury and inhibit renal fibrosis in rats with diabetic nephropathy induced by STZ,which might be related to the up-regulating of the expression of BMP-7 and the down-regulating the expression of TGF-β1 expression in kidney tissues.