达格列净对2型糖尿病肾病肾纤维化及TGF-β_(1)/p38MAPK通路的影响  

Effects of dapagliflozin on renal fibrosis and TGF-β_(1)/p38MAPK pathway in type 2 diabetic nephropathy

作　　者：张晨 倪林[1] 孙月飞 Zhang Chen;Ni Lin;Sun Yuefei(Department of Endocrinology,The First People's Hospital of Huzhou,Huzhou 313000,Zhejiang Province,China)

机构地区：[1]湖州市第一人民医院内分泌科,湖州313000

出　　处：《中国基层医药》2025年第1期7-13,共7页Chinese Journal of Primary Medicine and Pharmacy

基　　金：浙江省湖州市科技计划(2022GYB26)。

摘　　要：目的探讨达格列净对2型糖尿病肾病(T2DN)患者肾纤维化的治疗作用及相关机制。方法采用随机对照研究,选取湖州市第一人民医院2021年4月至2023年5月收治的T2DN患者152例,按照随机数字表法分为观察组、对照组各76例。对照组接受常规降糖治疗,观察组在对照组基础上接受达格列净治疗,两组治疗3个月。检测两组治疗前后糖化血红蛋白、血糖、肾功能指标和肾纤维化指标[透明质酸(HA)、Ⅳ型胶原(Ⅳ-C)、Ⅲ型前胶原(PCⅢ)、层粘连蛋白(LN)],并检测患者外周血转化生长因子β_(1)(TGF-β_(1))、p38MAPK通路[磷酸化细胞外调节蛋白激酶(p-ERK)、磷酸化P38丝裂原活化蛋白激酶(p-P38)和磷酸化c-JunN端激酶(p-JNK)]磷酸化、炎症因子[白细胞介素6(IL-6)、白细胞介素1β(IL-1β)、环氧化酶2(COX-2)]水平。采用转录组测序对患者肾脏活检样本总RNA进行建库测序。结果治疗后,观察组HA、LN、Ⅳ-C、PCⅢ分别为(167.42±17.91)μg/L、(106.10±14.57)μg/L、(95.98±10.03)μg/L、(89.38±9.75)μg/L,均低于对照组的(243.17±24.38)μg/L、(147.43±17.09)μg/L、(147.71±14.59)μg/L、(121.81±14.88)μg/L(t=21.83、16.04、25.47、15.89,均P<0.001);观察组IL-6、IL-1β、COX-2、TGF-β_(1)、p-ERK、p-P38和p-JNK蛋白水平均低于对照组(t=9.45、3.49、11.30、6.11、4.26、4.21、2.04,均P<0.05)。转录组测序富集分析显示“纤维连接”“炎症反应”和“TGF-β_(1)/P38 MAPK信号通路”为差异信号通路。观察组肾脏活检样本TGF-β_(1)、p-ERK、p⁃P38蛋白水平分别为(0.38±0.15)、(0.17±0.10)、(0.58±0.18),均低于对照组的(0.16±0.10)、(0.07±0.02)、(0.19±0.11)(t=2.99、2.40、4.53,均P<0.05)。观察组总有效率为93.43%(71/76),高于对照组的81.58%(62/76)(χ^(2)=7.02,P=0.030)。结论达格列净对T2DN患者肾纤维化具备良好治疗作用,其可抑制患者TGF-β_(1)/p38MAPK信号表达及炎症反应。Objective To investigate the therapeutic effects of dapagliflozin on renal fibrosis in patients with type 2 diabetic nephropathy(T2DN)and the underlying mechanisms involved.Methods A randomized controlled study was conducted involving 152 patients with T2DN who received treatment at The First People's Hospital of Huzhou from April 2021 to May 2023.The patients were divided into an observation group and a control group,with 76 participants in each group,using a random number table method.The control group received conventional hypoglycemic therapy,while the observation group received dapagliflozin in addition to the conventional hypoglycemic therapy.Both groups were treated for 3 months.Before and after treatment,glycated hemoglobin,blood glucose,renal function indicators,and renal fibrosis markers(hyaluronic acid,typeⅣcollagen,typeⅢprocollagen,and laminin)were measured.Additionally,the levels of transforming growth factor-beta 1(TGF-β1),phosphorylated p38 mitogen-activated protein kinase(MAPK)pathway components[phosphorylated extracellular signal-regulated kinase(p-ERK),phosphorylated p38 mitogen-activated protein kinase(p-P38),phosphorylated c-Jun N-terminal Kinase(p-JNK)],and inflammatory factors(interleukin-6,interleukin-1 beta,and cyclooxygenase-2)in the patients'peripheral blood were measured.Transcriptome sequencing was performed to construct libraries and sequence the total RNA from kidney biopsy samples of the patients.Results After treatment,the levels of hyaluronic acid,laminin,typeⅣcollagen,and typeⅢprocollagen in the observation group were(167.42±17.91)μg/L,(106.10±14.57)μg/L,(95.98±10.03)μg/L,and(89.38±9.75)μg/L,respectively.These values were significantly lower than those in the control group[(243.17±24.38)μg/L,(147.43±17.09)μg/L,(147.71±14.59)μg/L,and(121.81±14.88)μg/L,t=21.83,16.04,25.47,15.89,all P<0.001].The levels of interleukin-6,interleukin-1 beta,cyclooxygenase-2,TGF-β1,and p-ERK,p-P38,and p-JNK in the observation group were significantly lower than those in the con

关 键 词：糖尿病 2型 糖尿病肾病 肾 纤维化 转化生长因子β_(1) P38丝裂原活化蛋白激酶类 血糖 炎症趋化因子类 达格列净 

分 类 号：R692[医药卫生—泌尿科学] R587.2[医药卫生—外科学]