Kidney Development Of Intrauterine Growth Restriction Fetus And Associated Mechanisms

The morbidity and mortality of hypertension and kidney disease are increasing. It has been thought for a long time that heredity and environment play an important role in the development of these diseases. However, in recent years, a lot of epidemiologic studies have considered the suboptimal intrauterine environment can induce fetal development programming, leading to increased risk of predisposing hypertension and kidney disease, and thus putting forth the provocative hypothesis of fetal programming or developmental plasticity of adult disease. The kidney, because of its most sensitive to adverse insult, is the central organ of fetal programming, yet, related studies mainly focus on the animal models of FGR, human study is very limited. Hence, combined with the newest international progression, the first part of this study is about to study the kidney development of FGR, determining the nephron numbers, and its association with birth weight. The second part will investigate the possible mechanisms leading to these changes, in order to provide theory basis for low birth weight used as a clinical marker for congenital deficit in nephron number. The third part will proceed to evaluate FGR fetal kidney development using ultrasound, so as to find a new way to monitor high risk fetus early.In the first part, collecting fetal kidney tissues of FGR and nor-FGR. Nephron number are determined using an adaptation of the acid maceration method, calculating kidney weight and volume, and to analyze the correlation of nephron number with the birth weight.In the second part, investigating the possible mechanisms of leading to low nephron number. TUNEL method is used to detect the apoptosis in kidney, the protein expression of Bcl-2 and Bax are studied with immunohistochemisty. Using Real-time PCR and Western Blotting, the main components of RAS are analysed in the mRNA and protein levels, respectively.In the third part, ultrasound is used to evaluate fetal growth indexes, including biparietal diameter, head circumference, abdomen circumference and femur length; fetal kidney length, width and depth are measured, and kidney volume is calculated in order to know the relationship of kidney size and FGR. Results:The first part:the study of kidney developmentFGR fetal kidney weight, kidney volume and nephron number are all decreased compared with control group, the differences are significant, and fetal birth weight and nephron number are positively correlated(r= 0.809, P< 0.001), according to regression coefficient, nephron number increases about 170,042 averagely, when birth weight raises 1 kg.The second part:approaching the possible mechanisms of low nephron numberThe apoptosis in the FGR fetal kidney is significantly increased(P< 0.01), the protein expression of Bax increased and Bcl-2 decreased obviously(P< 0.01). Kidney renin of FGR fetus is significantly decreased, at mRNA and protein levels(P< 0.001), and the same for angiotensinogen, when compared with control.The third part:Evaluating FGR fetal kidney development using ultrasoundBiparietal diameter, abdomen circumference and femur length of FGR fetus are all smaller than control group, the differences are significant(P< 0.01). The kidney length and kidney volume of FGR fetus are also decreased, significantly(P< 0.01).Conclusions:1. There is low nephron number in FGR fetus, the significantly positive relationship is found between birth weight and nephron number, the number of nephron is about 170,042 increase every 1kg increase in birth weight. This shows that the adverse intrauterine environment can lead to congenital deficit in nephron number and low birth weight. Low birth weight can make as a clinical marker of kidney development defect and a predictive index to predispose to adult diseases. Accordingly, protection of kidney should begin from in-utero, and emphasizing the importance of antepartum monitoring to fetal health.2. The increased apotosis in FGR fetal kidney leading to low nephron number, smaller kidney volume, changes the morphology of kidney.3. The main components of RAS, renin and angiotensinogen are all low expression in FGR fetal kidney, whether mRNA or protein level, this suggests that adverse intrauterine environment induces the change of blood pressure regulation system RAS, leading to not only kidney defect congenitally, but also setting point of blood pressure in intrauterine, the onset of hypertension may begin from intrauterine, so supporting the hypothesis that FGR is associated with congenital low nephron number and later hypertension.4. Ultrasound evaluating of FGR fetal kidney length and volume demonstrates the relationship between the adverse intrauterine environment and kidney size, suggesting kidney size may be used as a surrogate marker of nephron number and a indirection index of kidney development, and ultrasound can be used to screen the high risk fetus.