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-β_1/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24 h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-β_1、Samd6、BMP7、α-SMA、E-Cadherin m RNA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 m RNA及蛋白的表达量增加,TGF-β_1和α-SMA m RNA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-β_1/Samd6/BMP7信号通路有关,这为DKD"肾痿"学说提供了新的实验依据。
Objective:To explore the protective effect and potential mechanisms of danshen root(Salvia miltiorrhiza Bge.,S.miltiorrhiza) and its extracts for the treatment of diabetic nephropathy(DN).Methods:Preclinical studies of S.miltiorrhiza and its extracts on DN were systematically searched in nine databases.The primary outcomes were blood glucose,kidney function,proteinuria,and renal histopathology.The secondary outcomes included the related mechanisms.The methodological quality of animal studies was assessed based on the risk of bias tool of the Systematic Review Centre for Laboratory Animal Experimentation(SYRCLE) for animal studies.Meta-analysis was performed using R software(version 4.1.2).Results:Twenty-nine animal experimental studies that met the eligibility criteria were included in this study.Compared to the control group,S.miltiorrhiza reduced the serum creatinine,blood urea nitrogen,24-h urine protein,24-h urine albumin,blood glucose,and kidney index(kidney weight/body weight),and alleviated renal pathological damage.In terms of the mechanism of action,compared to the control group,S.miltiorrhiza reduced the levels of transforming growth factor β1,collagen Ⅳ,malondialdehyde,tumor necrosis factor α,interleukin-6,and monocyte/macrophage(ED-1),and increased the levels of superoxide dismutase,glutathione peroxidase,nuclear factor E2-related factor 2,and heme oxygenase-1.Conclusion:The existing evidence shows that S.miltiorrhiza has beneficial effects on the animal model of DN,and its mechanism is mainly related to improving kidney fibrosis,oxidative stress,and inflammatory response.
