神经轴突导向因子1及其受体结直肠癌缺失基因在糖尿病肾脏疾病发生发展中的作用及机制研究  

The role and mechanism of NTN-1 and its receptor deleted in colorectal cancer in the pathogenesis of diabetic kidney disease

作　　者：陈瑜[1] 李云肖 马晓军[3] 周源 吴世卫[1] CHEN Yu;LI Yunxiao;MA Xiaojun(Department of Biochemistry and Molecular Biology,Shanxi University of Chinese Medicine,Xianyang 712046,China)

机构地区：[1]陕西中医药大学生物化学与分子生物学教研室,咸阳712046 [2]陕西中医药大学人体解剖学教研室,咸阳712046 [3]陕西中医药大学医学生物实验中心,咸阳712046

出　　处：《中国糖尿病杂志》2022年第7期533-539,共7页Chinese Journal of Diabetes

基　　金：国家自然科学基金(82004170)。

摘　　要：目的 探讨神经轴突导向因子1(NTN-1)及其受体结直肠癌缺失基因(DCC)在DKD发生发展中的作用及机制。方法 野生型雄性C57BL/6小鼠随机分为野生型对照组(WT-Con)、WT-DKD组、WT-DKD+NTN-1组,DCC-/-雄性小鼠随机分为DCC敲除(KO)对照组(KO-Con)、KO-DKD组、KO-DKD+NTN-1组,每组各8只。采用高脂喂养+STZ腹腔注射建立DKD模型,给予重组NTN-1尾静脉注射干预,比较各组血肌酐(Scr)、BUN、24 h尿蛋白(24 h UP)、肾脏病理改变、细胞凋亡率、NTN-1、DCC、裂孔膜肾病蛋白(Nephrin)、活化型半胱氨酸天冬氨酸蛋白酶3(Cleaved caspase-3)蛋白表达水平、TNF-α、IL-1β、IL-6含量。结果 与WT-Con组比较,WT-DKD组肾脏出现DKD病理改变,Scr、BUN、24 hUP及TNF-α、IL-1β、IL-6含量、细胞凋亡率、Cleaved caspase-3表达水平升高(P<0.05),NTN-1、DCC、Nephrin表达水平降低(P<0.05)。与WT-DKD组比较,WT-DKD+NTN-1组肾脏病理改变减轻,Scr、BUN、24 hUP及TNF-α、IL-1β、IL-6含量、细胞凋亡率、Cleaved caspase-3表达水平降低(P<0.05),NTN-1、Nephrin表达水平升高(P<0.05)。与WT-DKD+NTN-1组比较,KO-DKD+NTN-1组肾脏病理改变加重,Scr、BUN、24 h UP及TNF-α、IL-1β、IL-6含量、细胞凋亡率、Cleaved caspase-3表达水平升高(P<0.05),NTN-1、Nephrin表达水平降低(P<0.05)。结论 NTN-1通过受体DCC在DKD发病过程中起保护作用,抑制炎症反应及细胞凋亡是与其保护作用相关的分子机制。Objective To investigate the role and mechanism of Netrin-1(NTN-1)and its receptor deleted in colorectal cancer(DCC)in the pathogenesis of diabetic kidney disease(DKD).Methods Wild type male C57BL/6 mice were randomly divided into wild type(WT)-control group(WT-Con),WT-DKD group and WT-DKD+NTN-1 group. DCC-/-male mice were randomly divided into DCC knockout(KO)control group(KO-Con),KO-DKD group and KO-DKD+NTN-1 group,each group contained 8 mice.The DKD model was established by high fat feeding and intraperitoneal injection of streptozotocin,and treated with intravenous injection of recombinant NTN-1. Thenserum creatinine(Scr),blood urea nitrogen(BUN),24 hour urinary protein(24 hUP),renal pathological changes,apoptosis rate,expression of NTN-1,DCC,Nephrin,cleaved caspase-3,contents of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),interleukin-6(IL-6)were compared among the groups.Results Compared with WT-Con group,the pathological changes of DKD were found,Scr,BUN,24 h UPro and the contents of TNF-α,IL-1β,IL-6,the apoptosis rate,the expression of Cleaved caspase-3 expression in kidney increased(P<0. 05),while the expression of NTN-1,DCC and Nephrin in kidney decreased in WT-DKD group(P<0. 05). Compared with WT-DKD group,the pathological changes of kidney reduced,Scr,BUN,24 hUPro and the contents of TNF-α,IL-1β,IL-6,the apoptosis rate,the expression of cleaved caspase-3 expression in kidney decreased(P<0. 05),while the expression of NTN-1 and Nephrin in kidney increased in WT-DKD+NTN-1group(P<0. 05). Compared with WT-DKD+NTN-1 group,the pathological changes of kidney aggravated,Scr,BUN,24 hUPro and the contents of TNF-α,IL-1β,IL-6,the apoptosis rate,the expression of Cleaved caspase-3 expression in kidney increased(P<0. 05),while the expression of NTN-1 and Nephrin in kidney decreased in KO-DKD+NTN-1 group(P<0. 05).Conclusion NTN-1 plays a protective role in the pathogenesis of DKD through its receptor DCC. Inhibition of inflammation and apoptosis is the molecular mechanism related to this protectiv

关 键 词：糖尿病肾脏疾病 神经轴突导向因子1 结直肠癌缺失基因 炎症反应 细胞凋亡 

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