angiotensinogen and Fetal-Growth-Retardation

Fetal growth restriction (FGR) is a pregnancy complication wherein the foetus fails to reach its growth potential. The renin-angiotensin system (RAS) is a critical regulator of placental function, controlling trophoblast proliferation, angiogenesis and blood flow. The RAS significantly influences uteroplacental blood flow through the balance of its vasoconstrictive and vasodilatory pathways. Although the RAS is known to be dysregulated in placentae from women with preeclampsia, the expression of the RAS has not yet been studied in pregnancies compromised by FGR alone. This study investigated the mRNA expression and protein levels of RAS components in placentae from pregnancies compromised by FGR. Angiotensin II type 1 receptor (AGTR1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were reduced in FGR placentae compared with control (P = 0.012 and 0.018 respectively). Neprilysin (NEP) mRNA expression was lower in FGR placentae compared with control (P = 0.004). mRNA levels of angiotensinogen (AGT) tended to be higher in FGR placentae compared with control (P = 0.090). Expression of prorenin, AGT, angiotensin-converting enzyme (ACE) or ACE2 proteins were similar in control and FGR placentae. The renin-AGT reaction is a first order reaction so levels of expression of placental AGT determine levels of Ang II. Decreasing levels of ACE2 and/or NEP by limiting the production of Ang-(1-7), which is a vasodilator, and increasing placental Ang II levels (vasoconstrictor) may result in an imbalance between the vasoconstrictor and vasodilator arms of the placental RAS. Ultimately this dysregulation of the placental RAS could lead to reduced placental perfusion that is evident in FGR.

Topics: Angiotensin-Converting Enzyme 2; Angiotensinogen; Female; Fetal Growth Retardation; Gene Expression Regulation; Humans; Infant, Newborn; Infant, Small for Gestational Age; Neprilysin; Peptidyl-Dipeptidase A; Placenta; Pregnancy; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Topics: Angiotensinogen; Animals; Blood Pressure; Caloric Restriction; Creatinine; Denervation; Female; Fetal Growth Retardation; Hypertension; Kidney; Male; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Sympathetic Nervous System

The purpose of the study was to characterize changes in apoptosis and the renin-angiotensin system (RAS) in fetal growth restriction (FGR).. Fetuses were collected from patients who visited our hospital to either terminate or abort their pregnancy. Kidneys of fetuses which suffered with FGR, (n=11) at gestational age of 33.4±0.5 weeks and those from non-FGR (n=12) at gestational age of 34.3±0.9 weeks were collected. TUNEL, Bax and Bcl-2 staining were examined. The number of nephrons was also counted. Both protein and mRNA levels of renin and angiotensinogen were analyzed. Ultrasound was applied to measure fetus parameters including biparietal diameter, head circumference, circumference of abdomen, and femur length.. The number of nephrons was positively correlated with fetal weight at termination. Kidneys in the FGR group presented more apoptotic cells than those in the non-FGR group. Renin and angiotensinogen both decreased in the FGR group. Ultrasound revealed that biparietal diameter, abdomen circumference, femur length, and birth weight were all reduced in the FGR group compared with the non-FGR group. Kidney size was also restricted in the FGR group as indicated by ultrasound.. Renal apoptosis might contribute to the reduction of nephrons, and ultrasound plays a vital role in early diagnosis of developmental origins of health and disease (DOHAD).

Topics: Adult; Angiotensinogen; Apoptosis; Female; Fetal Growth Retardation; Fetus; Humans; In Situ Nick-End Labeling; Kidney; Organ Size; Pregnancy; Renin; Renin-Angiotensin System; RNA, Messenger; Ultrasonography, Prenatal

Kidney development is key to the onset of hypertension and cardiovascular diseases in adults, and in the fetal stage will be impaired by a lack of nutrients in utero in animal models. However, few human studies have been performed.. Kidney samples from fetuses in a fetal growth restriction (FGR) environment were collected and the morphological characteristics were observed. Potentially molecular mechanisms were explored by analyzing apoptosis and kidney-development related gene expression.. The results indicated that no malformations were observed in the kidney samples of the FGR group, but the mean kidney weight and volume were significantly decreased. Moreover, the ratio of apoptotic cells and Bax-positive cells was increased and the ratio of Bcl-2-positive cells was decreased in the FGR group, indicating potential apoptosis induction under an in utero FGR environment. Finally, aberrant expression of renin and angiotensinogen indicated potential kidney functional abnormalities in the FGR group.. Our study suggested increased apoptosis and decreased renin and angiotensinogen expression during human kidney development in an FGR environment. The current results will be helpful to further explore the molecular mechanism of FGR and facilitate future studies of hypertension and cardiovascular diseases and the establishment of preventive methods.

Topics: Adult; Angiotensinogen; Apoptosis; Birth Weight; Case-Control Studies; Female; Fetal Growth Retardation; Fetus; Gene Expression Profiling; Gene Expression Regulation, Developmental; Humans; Kidney; Pregnancy; Renin; RNA, Messenger; Young Adult

Few studies have addressed the growing concerns of chronic kidney diseases in children with intrauterine growth restriction (IUGR). Therefore, the purpose of this study was to evaluate long-term kidney dysfunction and determine if urinary angiotensinogen (AGT) was suitable as a novel early biomarker for kidney dysfunction in IUGR offspring.. Pregnant rats underwent bilateral uterine artery ligation, and as a control group, sham surgeries were performed.. The birth weight was reduced, the urinary AGT to creatinine ratio was significantly higher at week 20, and urinary protein levels were significantly higher at week 32 in IUGR rats than in control rats. On the other hand, the histological findings at week 32 revealed long-term kidney dysfunction, more severe glomerulosclerosis, and greater glomerular diameters in IUGR rats. Moreover, AGT mRNA expression and immunohistological staining were significantly increased in IUGR rats; this suggests that the intrarenal renin-angiotensin system (RAS) contributes to renal dysfunction of IUGR offspring.. Urinary AGT elevation prior to urinary protein levels suggests that AGT is an early biomarker. At week 32, kidney dysfunction was severe in IUGR rats and intrarenal RAS appeared to be one of the causes.

Topics: Age Factors; Angiotensinogen; Animals; Biomarkers; Birth Weight; Creatinine; Disease Models, Animal; Early Diagnosis; Female; Fetal Growth Retardation; Kidney; Kidney Diseases; Ligation; Organ Size; Predictive Value of Tests; Pregnancy; Prenatal Exposure Delayed Effects; Proteinuria; Rats, Sprague-Dawley; Renin-Angiotensin System; Up-Regulation; Uterine Artery

The renin-angiotensin (Ang) system is important during placental development. Dysregulation of the renin-Ang system is important in preeclampsia (PE). Female rats transgenic for the human angiotensinogen gene crossed with males transgenic for the human renin gene develop the PE syndrome, whereas those of the opposite cross do not. We used this model to study the role of Ang II in trophoblast invasion, which is shallow in human PE but deeper in this model. We investigated the following groups: PE rats, opposite-cross rats, Ang II-infused rats (1000 ng/kg per day), and control rats. Ang II infusion increased only circulating Ang II levels (267.82 pg/mL), opposite cross influenced only uteroplacental Ang II (13.52 fmol/mg of protein), and PE increased both circulating (251.09 pg/mL) and uteroplacental (19.24 fmol/mg of protein) Ang II. Blood pressure and albuminuria occurred in the models with high circulating Ang II but not in the other models. Trophoblast invasion increased in PE and opposite-cross rats but not in Ang II-infused rats. Correspondingly, uterine artery resistance index increased in Ang II-infused rats but decreased in PE rats. We then studied human trophoblasts and villous explants from first-trimester pregnancies with time-lapse microscopy. Local Ang II dose-dependently increased migration by 75%, invasion by 58%, and motility by 282%. The data suggest that local tissue Ang II stimulates trophoblast invasion in vivo in the rat and in vitro in human cells, a hitherto fore unrecognized function. Conceivably, upregulation of tissue Ang II in the maternal part of the placenta represents an important growth factor for trophoblast invasion and migration.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Brain; Cell Movement; Crosses, Genetic; Female; Fetal Growth Retardation; Humans; Liver; Male; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Rats; Renin; Trophoblasts; Up-Regulation; Uterus

We tested the hypothesis that maternal protein deprivation during gestation results in changes in expression of the systemic renin-angiotensin system in fetal mice. Fetal weight was decreased significantly as a consequence of 50% maternal protein deprivation during second half of gestation. In fetal liver, angiotensinogen protein expression was reduced significantly despite a significant increase in messenger RNA (mRNA). In fetal kidneys, both mRNA and protein levels of renin were increased significantly. In the lungs, we observed a decrease in both angiotensin-converting enzyme I and II mRNA expression, whereas protein expression of both isoforms was increased significantly. The fetal heart showed significant increases in expression of angiotensin II type 1 (AT-1) and type 2 (AT-2) receptors mRNA. Protein expression of AT-1 receptors increased, while that of AT-2 receptors decreased. We conclude that maternal low-protein diet during gestation leads to significant changes in expression of the systemic renin-angiotensin system in fetal mice and may be important in the genesis of hypertension in the adult.

Topics: Adaptor Proteins, Signal Transducing; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Dietary Proteins; Female; Fetal Growth Retardation; Gene Expression Regulation, Developmental; Hypertension; Mice; Peptidyl-Dipeptidase A; Pregnancy; Pregnancy Complications; Protein-Energy Malnutrition; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System; RNA, Messenger

Previous studies have shown that intrauterine growth restriction (IUGR) can impair nephrogenesis, but uncertainties remain about the importance of the gestational timing of the insult and the effects on the renal renin-angiotensin system (RAS). We therefore hypothesized that induction of IUGR during late gestation alters the RAS, and this is associated with a decrease in nephron endowment. Our aims were to determine the effects of IUGR induced during the later stages of nephrogenesis on 1) nephron number; 2) mRNA expression of angiotensin AT(1) and AT(2) receptors, angiotensinogen, and renin genes in the kidney; and 3) the size of maculae densae. IUGR was induced in fetal sheep (n = 7) by umbilical-placental embolization from 110 to 130 days of the approximately 147-day gestation; saline-infused fetuses served as controls (n = 7). Samples of cortex from the left kidney were frozen, and the right kidney was perfusion fixed. Total kidney volume, nephron number, renal corpuscle volume, total maculae densae volume, and the volume of macula densa per glomerulus were stereologically estimated. mRNA expression of AT(1) and AT(2) receptors, angiotensinogen, and renin in the renal cortex was determined. In IUGR fetuses at 130 days, body and kidney weights were significantly reduced and nephron number was reduced by 24%. There was no difference in renin, angiotensinogen, or AT(1) and AT(2) receptor mRNA expression levels in the IUGR kidneys compared with controls. We conclude that fetal growth restriction late in nephrogenesis can lead to a marked reduction in nephron endowment but does not affect renal corpuscle or macula densa size, or renal RAS gene expression.

Topics: Angiotensin II; Angiotensinogen; Animals; Body Weight; Erythrocyte Indices; Female; Fetal Growth Retardation; Fetal Weight; Fetus; Gene Expression; Gestational Age; Kidney; Nephrons; Organ Size; Pregnancy; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sheep

Placental insufficiency in the rat results in intrauterine growth restriction and development of hypertension in prepubertal male and female growth-restricted offspring. However, after puberty, only male growth-restricted offspring remain hypertensive, whereas female growth-restricted offspring stabilize their blood pressure to levels comparable to adult female controls. Because female rats reach their maximum levels of estrogen at puberty, we hypothesize that estrogen may be a factor involved in the stabilization of blood pressure in adult female growth-restricted offspring. At 10 weeks of age, female control and growth-restricted offspring underwent ovariectomy or sham surgery and insertion of a telemetry probe. Mean arterial pressure was similar at 16 weeks of age between control (123+/-4 mm Hg) and growth-restricted offspring (122+/-2 mm Hg); however, ovariectomy led to a significant increase in blood pressure in growth-restricted offspring (140+/-2 mm Hg; P<0.05 versus intact counterpart) with no significant effect in controls (124+/-1 mm Hg). Estrogen replacement by subcutaneous minipellet initiated at 14 weeks of age in a subset of ovariectomized control and growth-restricted offspring reversed the effect of ovariectomy on blood pressure in growth-restricted offspring at 16 weeks of age (111+/-3 mm Hg; P<0.05 versus ovariectomized counterpart); renin angiotensin system blockade also abolished ovariectomy-induced hypertension in female growth-restricted offspring (106+/-2 mm Hg; P<0.05 versus ovariectomized counterpart). Therefore, sex differences are observed in this model of fetal programmed hypertension, and results from this study suggest that estrogen contributes to normalization of blood pressure in adult female growth-restricted offspring.

Topics: Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Birth Weight; Blood Pressure; Estradiol; Estrogens; Female; Fetal Development; Fetal Growth Retardation; Hypertension; Kidney; Male; Peptidyl-Dipeptidase A; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; RNA, Messenger; Sex Characteristics; Sexual Maturation

Little is known about an in vivo significance of angiotensin II Type-1 receptor (AT1) for pregnancy-associated diseases, including hypertension and intrauterine growth retardation (IUGR). We previously demonstrated that female mice carrying the human angiotensinogen gene (hAG+/+), when mated with human renin transgenic (hRN+/+) male mice, displayed hypertension in late pregnancy due to secretion of human renin from the fetal side into the maternal circulation. In the present study, to investigate a role for AT1 in pregnancy-associated hypertension, we generated a new strain of hAG+/+/mAT1a-/- mice by genetically deleting the AT1a gene from hAG+/+ mice. When mated with hRN+/+ male mice, excessive increases in human renin, angiotensin, and plasma renin activity were detected in the plasma of pregnant hAG+/+/mAT1a-/- mice as found in that of pregnant hAG+/+ mice. Surprisingly, however, blood pressure of hAG+/+/mAT1a-/- mice was not elevated in late pregnancy despite the presence of AT1b, a subtype of AT1. The maternal and fetal defects, such as cardiac and placental abnormalities, and IUGR observed in pregnant hypertensive hAG+/+ mice were not recognized in pregnant hAG+/+/mAT1a-/- mice. The limited term administration of AT1 antagonists to hypertensive hAG+/+ mice in late pregnancy dramatically improved hypertension and IUGR, showing the clinical importance of AT1a.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Blood Pressure; Cardiomegaly; Crosses, Genetic; Female; Fetal Growth Retardation; Gene Deletion; Humans; Hypertension; Male; Mice; Mice, Transgenic; Placenta; Pregnancy; Receptor, Angiotensin, Type 1; Renin

Intrauterine growth restriction has been associated with failed maternal physiologic changes such as abnormal spiral artery remodeling and reduced maternal blood volume. A polymorphism of angiotensinogen Thr235 has been considered a risk factor for preeclampsia. We genotyped maternal and fetal deoxyribonucleic acid (DNA) for angiotensinogen Thr235 to estimate whether the polymorphism is also a risk factor for intrauterine growth restriction.. We examined maternal blood DNA in 174 patients with intrauterine growth restriction and 60 patients with both preeclampsia and intrauterine growth restriction. The control group comprised 400 consecutive cases of women with term pregnancies and infants with birth weight between the fifth and 95th percentiles. We also examined 162 DNA samples from fetal blood with intrauterine growth restriction for the Thr235 polymorphism, and 240 normal fetuses were used as the control group. The angiotensinogen genotype was determined using mutagenically separated polymerase chain reaction. The products were size fractionated on an agarose gel. Angiotensinogen genotypes were divided into three groups: MM (homozygous for angiotensinogen Met235 allele), TT (homozygous for angiotensinogen Thr235 allele), and MT (heterozygous).. Maternal genotyping revealed a significantly higher Thr235 allele frequency in intrauterine growth restriction (.60) and preeclampsia/intrauterine growth restriction (.63) than in the control group (.36) (P <.001). Fetal genotyping revealed a Thr235 allele frequency of.59 in intrauterine growth restriction fetuses, as compared with the control group (.38) (P <.001).. Maternal and fetal angiotensinogen Thr235 genotypes are associated with an increased risk of intrauterine growth restriction in our study population. The angiotensinogen Thr235 allele may predispose women to deliver growth-restricted fetuses.

Topics: Adolescent; Adult; Alleles; Angiotensinogen; Base Sequence; Case-Control Studies; Female; Fetal Growth Retardation; Gene Frequency; Genetic Variation; Genotype; Humans; Molecular Sequence Data; Polymerase Chain Reaction; Polymorphism, Genetic; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Prenatal Care; Prenatal Diagnosis; Prevalence; Probability; Reference Values; Risk Assessment; Sensitivity and Specificity

The SHHF/Mcc-fa(cp) (spontaneous hypertension and heart failure) rat is advanced as a novel and suitable non-primate model of pregnancy-associated hypertension and fetal growth restriction because it simultaneously has spontaneous pregnancy-associated hypertension, small for gestational age (SGA) offsprings, and altered placental gene expression. Pregnancy-associated hypertension is a major contributor to maternal and fetal morbidity and mortality with the potential to result in maternal death and the need for iatrogenic preterm delivery. It has been reported to develop spontaneously in humans, but not in animals; consequently, progress in identifying the cause and pathogenesis of this disorder has been hampered. Spontaneous hypertension and heart failure rats develop hypertension spontaneously as they age, therefore we sought to determine whether these rats developed hypertension and SGA offsprings during pregnancy. Our results show that systolic blood pressure (BP) increased >40 mm Hg by the end of the first trimester and remained at this elevated level for the remainder of pregnancy, but decreased after parturition. Placenta weights of SHHF rats (0.60 +/- 0.02 g, n = 36) were significantly higher than Wistar-Kyoto (WKY) rats (0.42 +/- 0.01 g, n = 22, P < .05), but pup weights were significantly lower (2.68 +/- 0.06 g for SHHF rats compared to 3.24 +/- 0.06 g for WKY controls, P < .05). Histologic examination revealed pathologic lesions in neither heart, liver, placenta, nor kidney. L-Arginine administered in drinking water prevented the elevation of BP, particularly during the third trimester. Placentas from SHHF rats displayed altered expression of several genes whose protein products have been implicated in preeclampsia, including serotonin receptor, sodium channel, carbonic anhydrase, estrogen receptor regulator, major histocompatibility complex proteins, superoxide dismutase, and angiotensiogen. In addition, gene expression profiling showed alteration of a number of subcellular putative myristoylproteins not previously associated with preeclampsia, particularly those engaged in post-translational modifications in the placenta. Thus, SHHF rats may be a valuable tool, because it simultaneously has spontaneous pregnancy-associated hypertension, SGA offsprings, and altered placental gene expression.

Topics: Angiotensinogen; Animals; Birth Weight; Disease Models, Animal; Female; Fetal Growth Retardation; Fetal Weight; Gene Expression Profiling; Hypertension; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Protein Processing, Post-Translational; Rats; Rats, Inbred WKY; Rats, Mutant Strains