孕期咖啡因暴露所致雌性子代胎鼠肾脏宫内发育迟缓及其发生机制  

Renal developmental retardation and the underlying mechanism induced by prenatal caffeine exposure in female fetal rats

作　　者：万阳[1] 敖英[1,2] 李斌[3] 熊颖 孙朝霞[1] 胡霜霜[1] 汪晖[1,2] 

机构地区：[1]武汉大学基础医学院药理学系,湖北武汉430071 [2]武汉大学发育源性疾病湖北省重点实验室,湖北武汉430071 [3]武汉大学中南医院骨科,湖北武汉430071

出　　处：《中国药理学通报》2018年第2期213-219,共7页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 81430089;81001466)

摘　　要：目的观察孕期咖啡因暴露(PCE)♀胎肾发育病理学变化和皮质酮(CORT)处理对原代后肾间充质细胞基因表达的影响,探究PCE影响胎鼠肾脏发育的可能机制。方法受孕Wistar大鼠于孕9-20 d(GD 9-20)经口灌胃咖啡因(30、120 mg·kg^(-1)·d^(-1)),孕鼠于GD20处死,取♀胎鼠并收集肾脏,检测肾脏病理学变化和基因表达;在原代后肾间充质细胞上给予不同浓度CORT(250、500、1 000μg·L^(-1))处理24 h,检测细胞基因表达。结果与对照组相比,PCE组♀胎肾肾小球的球囊空虚,鲍曼囊腔变大,毛细血管网发育不良,GDNF/c-Ret信号通路抑制;CORT处理原代后肾间充质细胞下调AT_1R/AT_2R及GDNF/c-Ret信号通路的表达。结论 PCE♀胎鼠肾脏发育不良,其机制与PCE所致高血CORT下胎肾局部AT_1R/AT_2R及GDNF/c-Ret信号通路的表达抑制有关。To explore the effects of prenatal caffeine exposure( PCE) on fetal renal growth retardation and corticosterone on the gene expression of metanephric mesenchyme stem cells. Methods Pregnant Wistar rats were administered with caffeine( 30,120 mg·kg^(-1)) from gestational day 9 to 20. Female fetal kidney samples were collected for morphological observation and gene expression examination. The metanephric mesenchyme stem cells were harvested for cell culture,and renal related genes were detected after the treatment of corticosterone with different concentrations( 250,500,1 000 μg·L^(-1)) for 24 hours. Results Compared with the control group,the fetal kidneys in the PCE group displayed an enlarged Bowman's space and a shrunken glomerular tuft,accompanied with the repression of the gene expression of glial-cell-line-derived neurotrophic factor/tyrosine kinase receptor( GDNF/c-Ret) signaling pathway. The GDNF/c-Ret signaling pathway and angiotensin II receptor type 1( AT_1 R)/AT_2 R expression of metanephric mesenchyme stem cells also decreased in corticosterone groups.Conclusions PCE may induce dysplasia of female fetal kidneys. The potential mechanism is related to the repression of the gene expression of AT_1 R/AT_2 R and GDNF/c-Ret signaling pathway by PCE mediated by corticosterone in utero.

关 键 词：孕期咖啡因暴露 宫内发育迟缓 糖皮质激素 胎肾发育不良 血管紧张素Ⅱ1/2型受体 胶质源性神经营养因子/酪氨酸激酶受体信号通路 

分 类 号：R-332[医药卫生] R322.61