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目的研究宫内生长受限(IUGR)仔鼠肾组织中调控输尿管芽分支发生的关键因子细胞外信号调节激酶(ERK1/2)及下游基因Wnt4的表达与活性,探讨其与肾脏发育不良和高血压发生的关系。方法孕鼠随机分为对照组(n=30)和IUGR组(n=30),孕期低蛋白饮食法建立IUGR模型,自然分娩后部分新生仔鼠(0 d)处死取其双肾称重,其他仔鼠常规饲养。测定3周龄和8周龄仔鼠的肾指数、肾小球数目、肾功能和血压,采用蛋白印迹法测定出生0 d和3周仔鼠肾脏中ERK1/2和Wnt4蛋白水平和磷酸化水平,荧光定量反转录(RT)-PCR法检测其肾脏Wnt4 mRNA水平。结果新生和3周龄IUGR仔鼠体质量和肾质量均低于对照组,8周IUGR仔鼠体质量超过对照组,但肾指数依然降低,肾小球数目明显减少(Pa<0.05)。8周IUGR仔鼠血压升高、内生肌酐清除率(CCr)减低,且肾小球数目与血压呈负相关(Pa<0.05)。出生0 d和3周时IUGR仔鼠肾组织中ERK1/2磷酸化水平降低(Pa<0.05),Wnt4的表达水平始终低于同龄对照组(Pa<0.05)。结论在肾单位发生和生长成熟阶段,宫内蛋白营养不良的子代肾组织ERK蛋白活性降低及诱导Wnt4表达异常可能是肾小球数目减少、成年肾滤过率降低引发高血压易感的机制之一。
Objective To study the expression and activity of extracellular signal-regulated kinase (ERK1 / 2) and its downstream gene Wnt4, a key factor in the regulation of the bud of the ureter in renal tissue of neonatal rats with limited intrauterine growth (IUGR), and to investigate its relationship with dysplasia and high The relationship between blood pressure. Methods Pregnant mice were randomly divided into control group (n = 30) and IUGR group (n = 30). IUGR model was established by low protein diet during pregnancy. Some newborn offspring (0 d) Other offspring routine breeding. Kidney index, glomerular number, renal function and blood pressure were measured in pups aged 3 weeks and 8 weeks. The protein levels and phosphorylation levels of ERK1 / 2 and Wnt4 in kidneys of pups at 0 and 3 weeks of life were measured by Western blotting , And the level of Wnt4 mRNA in kidney was detected by fluorescence quantitative reverse transcription-PCR. Results The body weight and kidney mass of neonatal and 3-week-old IUGR offspring rats were lower than those of the control group. The body weight of IUGR offspring was higher than that of the control group at 8 weeks. However, the renal index was still decreased and the number of glomeruli was significantly decreased (P <0.05). After 8 weeks, the blood pressure of IUGR rats was increased, the creatinine clearance (CCr) decreased, and the number of glomeruli was negatively correlated with blood pressure (Pa <0.05). The levels of phosphorylated ERK1 / 2 in IUGR offspring were decreased (P <0.05) at 0 d and 3 d after birth, and the expression of Wnt4 was always lower than that of the same age control group (Pa <0.05). Conclusion In the stage of nephrongenesis and maturation, the decrease of ERK activity and the abnormal expression of Wnt4 in the progeny of uterine malnutrition may be the mechanism of reducing the number of glomeruli and reducing the susceptibility to hypertension caused by the decrease of adult renal filtration rate one.