目的：本研究主要探讨糖肾平对糖尿病肾病（DKD）KK-Ay小鼠肾脏保护作用及其对TGF-β₁/Samd6/BMP7信号通路的影响。方法：10只雌性C57BL/6J小鼠作为对照组。雌性10周龄KK-Ay小鼠60只，KK鼠料诱导10周后建立糖尿病肾病动物模型。模型小鼠按体质量和血糖区组分层随机法分为模型组、厄贝沙坦组与糖肾平小、中、大剂量组。厄贝沙坦组，糖肾平小、中、大剂量组均灌胃给药，正常组、模型组用等体积去离子水灌胃。每4 周称体质量和测24h尿蛋白定量。实验第26周，眼球取血并处死小鼠，称肾脏质量、测血糖，分离血清测BUN、Scr、TG、MDA、NO和SOD；HE染色和Mallory染色观察肾组织病理形态；原位杂交、免疫组化、Western blot检测肾组织TGF-β₁、Samd6、BMP7、α-SMA、E-Cadherin mRNA及蛋白表达。结果：与模型组比较，各治疗组体质量、肾质量/体质量、尿蛋白降低，其中糖肾平中、大剂量组有显著性差异（P<0.01）；肾脏病理损害明显减轻，FBG、血清BUN、Scr、TG 和MDA含量明显降低（P<0.01），NO、SOD含量明显增加（P<0.01），Samd6、BMP7和E-Cadherin mRNA及蛋白的表达量增加，TGF-β₁和α-SMA mRNA及蛋白的表达量减少，其中糖肾平大剂量组有显著性差异（P<0.01），糖肾平的治疗效果呈剂量依赖关系。结论：糖肾平对DKD KK-Ay小鼠肾脏保护及逆转肾小管上皮细胞转分化的作用，可能与下调氧化应激水平及调节TGF-β₁/ Samd6/BMP7信号通路有关，这为DKD“肾痿”学说提供了新的实验依据。

This study aimed to explore the renoprotective effects of Tangshenping on TGF-β₁/Samd6/BMP7 signaling pathway in KK-Ay mice with diabetic kidney disease(DKD).Ten female C57BL/6J mice were made up for the control group.Sixty female 10-week-old KK-Ay mice were used to establish the animal model of diabetic kidney disease with 10-week special food intake.Mice were randomly divided into the model group,the irbesartan group and the Tangshenping low-,medium- and high-dose groups depending on their body weight and blood glucose levels.The mice of the irbesartan group and Tangshenping low-,medium- and high-dose groups were intragastrically administered with irbesartan and Tangshenping,respectively,while the mice of the control group and the model group were treated with deionized water with the equal volume.24h urine protein quantification and body weight were tested every 4 weeks.At th e end of the 26th week,all the mice were sacrificed and the biochemical indicators,such as serum BUN,SCR,TG,MDA,SOD and NO were measured;while HE staining and Mallory staining were used to observe the pathological morphology of the kidney tissues,and in situ hybridization,immunohistochemistry and western blot to detect TGF-β₁,Samd6,BMP7,α-SMA,E-cadherin mRNA and protein expressions in the renal tissues.As a result,compared with the model group,it was found that the body weight,the ratio of kidney weight to body weight,and 24h albuminuria in all the treatment groups were reduced,and significant differences showed between Tangshenping medium- and high-dose groups(P<0.01);renal pathological damage was improved,the contents of FBG,serum BUN,Scr,TG and MDA were decreased significantly(P<0.01),while serum NO and SOD increased(P<0.01);the protein and mRNA expressions of Samd6,BMP7 and E-cadherin were enhanced,while the expressions of TGF-β₁ and α-SMA attenuated.These changes were especially obvious in the Tangshenping high-dose group(P<0.01).Moreover,the therapeutic effect of Tangshenping was dose dependent.In conclusion,it was demonstrated that Tangshenping protected and reversed the epithelial-mesenchymal transdifferentiation of renal tubular epithelial cells in DKD KK-Ay mice,which may be achieved via a reduction in oxidative stress and the regulation of TGF-β₁/Samd6/BMP7 signaling pathway.This study provided new experimental evidence for the theory of "kidney impotence" in DKD.

国家自然科学基金委面上项目（81373831）：基于“肾痿”组方的糖肾平干预糖尿病肾病肾小管上皮细胞转分化的分子机制研究，负责人：赵宗江。