达格列净调控p38丝裂原活化蛋白激酶通路对高糖诱导足细胞增殖、凋亡及炎症反应影响的研究  

Effect of Dapagliflozin on cell proliferation,apoptosis and inflammation of podocytes induced by high glucose via regulating p38 MAPK pathway

作　　者：王东 刘娟[2] 段瑞祥 张勇 胡春华 张海萍 赵会文 王小磊 WANG Dong;LIU Juan;DUAN Ruiriang(Department of Endocrinology,The Afiliated Endocrine and Metabolic Disease Hospital,Shandong First Medical University,Jinan 250000,China)

机构地区：[1]山东第一医科大学附属内分泌与代谢病医院内分泌科,济南250000 [2]济南市第五人民医院内分泌科

出　　处：《中国糖尿病杂志》2024年第2期117-124,共8页Chinese Journal of Diabetes

基　　金：国家自然科学基金(8190035252)。

摘　　要：目的 探讨达格列净通过p38丝裂原活化蛋白激酶(p38 MAPK)通路对高糖诱导的足细胞增殖及凋亡的影响。方法 将人肾小球足细胞(HGPC)分为正常对照(Con)组、低、中、高D-葡萄糖组(Glu 10、Glu 20、Glu 30)、高糖组(HG)、HG+低、中、高浓度达格列净组(HG+Dap 12.5、HG+Dap 25、HG+Dap 50)、HG+达格列净组(HG+Dap)、HG+抑制剂组(HG+SB 203580)、HG+达格列净+抑制剂组(HG+Dap+SB 203580)、达格列净+激活剂组(HG+Dap+C16-PAF),干预24 h,检测各组细胞活力、增殖率、凋亡率和相关因子水平。结果 与Con组比较,HG组IL-1β、TNF-α、细胞凋亡率、半胱氨酸天冬氨酸蛋白酶-3(Caspase-3)mRNA和蛋白表达、p53、p-p38 MAPK蛋白表达升高(P<0.05),细胞增殖率、细胞周期素D1(Cyclin D1)mRNA和蛋白表达降低(P<0.05)。与HG组比较,HG+Dap、HG+SB 203580组增殖率、Cyclin D1 mRNA和蛋白表达升高(P<0.05),IL-1β、TNF-α、细胞凋亡率、Caspase-3 mRNA和蛋白表达、p53、p-p38 MAPK蛋白表达降低(P<0.05)。与HG+Dap组比较,HG+Dap+SB 203580组细胞增殖率、Cyclin D1 mRNA和蛋白表达升高(P<0.05),IL-1β、TNF-α、细胞凋亡率、Caspase-3 mRNA和蛋白表达、p53、p-p38 MAPK蛋白表达降低(P<0.05),HG+Dap+C16-PAF组IL-1β、TNF-α、细胞凋亡率、Caspase-3 mRNA和蛋白表达、p53、p-p38 MAPK蛋白表达升高(P<0.05),细胞增殖率、Cyclin D1 mRNA和蛋白表达降低(P<0.05)。结论 达格列净可促进高D-葡萄糖环境下HGPC增殖,抑制细胞凋亡及炎症反应,其作用机制可能与抑制p38 MAPK通路信号转导相关。Objective To investigate the effect of Dapagliflozin on high glucose-induced podocyte proliferation and apoptosis through p38 mitogen-activated protein kinase(p38 MAPK)pathway.Methods Human glomerular podocytes(HGPC)were divided into control(Con)group,low/medium/high D-glucose(Glu 10,Glu 20,Glu 30)group,high glucose(HG)group,low/medium/high concentration Dapagliflozin(HG+Dap 12.5,HG+Dap 25,HG+Dap 50)group,Dapagliflozin(HG+Dap)group,inhibitor(HG+SB 203580)group,Dapagliflozin+inhibitor(HG+Dap+SB 203580)group and Dapagliflozin+activator(HG+Dap+C16-PAF)group.After 24 hours of intervention,the cell viability,proliferation rate,apoptosis rate and levels of related factors were tested.Results Compared with Con group,IL-1β,TNF-α,apoptosis rate,Caspase-3 mRNA and protein expression,p53,p-p38 MAPK protein expression were increased(P<0.05),while cell proliferation rate,Cyclin D1 mRNA and protein expression were decreased in HG group(P<0.05).Compared with HG group,the proliferation rate,Cyclin D1 mRNA and protein expression were increased(P<0.05),while IL-1β,TNF-α,apoptosis rate,Caspase-3 mRNA and protein expression,p53,p-p38 MAPK protein expression were decreased in the HG+Dap and HG+SB 203580 groups(P<0.05).Compared with HG+Dap group,cell proliferation rate,Cyclin D1 mRNA and protein expression were increased(P<0.05),while IL-1β,TNF-α,apoptosis rate,Caspase-3 mRNA and protein expression,p53,p-p38 MAPK protein expression were decreased in HG+Dap+SB 203580 group(P<0.05).In HG+Dap+C16-PAF group,IL-1β,TNF-α,apoptosis rate,Caspase-3 mRNA and protein expression,p53,p-p38 MAPK protein expression were increased(P<0.05),while cell proliferation rate,Cyclin D1 mRNA and protein expression were decreased(P<0.05).Conclusion Dagagliflozin can promote HGPC proliferation and inhibit apoptosis and inflammation in high D-glucose environment,and its mechanism may be related to the inhibition of p38 MAPK pathway signal transduction.

关 键 词：糖尿病肾脏疾病 人肾小球足细胞 达格列净 D-葡萄糖 p38丝裂原活化蛋白激酶通路 增殖 凋亡 炎症 

分 类 号：R587.2[医药卫生—内分泌] R692.9[医药卫生—内科学]