We have generated a transgenic model consisting of both the human renin and human angiotensinogen genes to study further the role played by the renin-angiotensin system in regulating arterial pressure. Transgenic mice containing either gene alone were normotensive, whereas mice containing both genes were chronically hypertensive. Plasma renin activity and plasma angiotensin II levels were both markedly elevated in the double transgenic mice compared with either single transgenic or nontransgenic controls. The elevation in blood pressure caused by the human transgenes was independent of the genotype at the endogenous renin locus and was equal in mice homozygous for the Ren-1 c allele or in mice containing one copy each of Ren-1 c , Ren-1 d , or Ren-2. Chronic overproduction of angiotensin II in the double transgenic mice resulted in a resetting of the baroreflex control of heart rate to a higher pressure without significantly changing the gain or sensitivity of the reflex. Moreover, this change was not due to the effects of elevated pressure itself since angiotensin-converting enzyme inhibition had minimal effects on the baroreflex in spontaneously hypertensive BPH-2 control mice, which exhibit non-renindependent hypertension. This double transgenic model should provide an excellent tool for further studies on the mechanisms of hypertension initiated by the renin-angiotensin system. ( J. Clin. Invest. 1996. 97:1047-1055.)
Angiotensin-(1-7) (Ang-[1-7]) is a bioactive component of the renin-angiotensin system, which has depressor, vasodilatory, and antihypertensive actions. In normal pregnancy, we questioned whether the known rise in plasma angiotensin II (Ang II) is counterbalanced by an increase in plasma Ang-(1-7) and whether Ang-(1-7) levels are decreased in preeclampsia and may thus be a factor involved in the development of hypertension. Nulliparous preeclamptic subjects, third-trimester normotensive pregnant subjects, and a nonpregnant group were enrolled (n = 15/group). Preeclamptic subjects had no previous history of hypertension or renal, connective-tissue, or metabolic disease, but at the time of delivery had significant hypertension (159 +/- 3/98 +/- 3 mmHg) and > or = 3+ proteinuria. Plasma Ang-(1-7) was increased by 51% in normal pregnancy (p < 0.05). Plasma Ang I, Ang II, and renin activity were also significantly elevated in normal pregnancy. In preeclamptic subjects, Ang-(1-7) was significantly decreased (p < 0.01) compared with normal pregnant subjects. All other components of the renin-angiotensin-aldosterone system, except serum angiotensin-converting enzyme, were reduced in preeclamptic subjects compared with normal pregnant subjects; only plasma Ang II remained elevated in preeclamptic compared with nonpregnant subjects. These studies demonstrate, for the first time, increased plasma Ang-(1-7) in normal pregnant subjects compared with nonpregnant subjects and decreased Ang-(1-7) in preeclamptic subjects compared with normal pregnant subjects. In preeclampsia the decreased plasma Ang-(1-7) in the presence of elevated Ang II is consistent with the development of hypertension.
Abstract-Preeclampsia remains a leading cause of maternal and fetal morbidity and mortality but has an unknown etiology. Women with elevated baseline blood pressure have an increased risk of this disorder. We hypothesized that BPH/5 mice, an inbred mouse strain with mildly elevated blood pressure, would develop a pregnancy-induced hypertensive syndrome. Nonpregnant female BPH/5 and C57BL/6 mice underwent thoracic aortic implantation of telemeters. After 7 days of recovery and 5 days of baseline mean arterial blood pressure (MAP) recording, strain-matched timed matings were carried out. MAP was recorded continuously during pregnancy and for 1 week after birth. In separate mice in metabolic cages, urinary protein was tracked, followed by renal histological analysis. Before pregnancy, the BPH/5 strain had elevated baseline MAP compared with the C57BL/6 strain, but both strains had similar total urinary protein levels and renal histology. MAP remained stable in both groups during the first 2 weeks of pregnancy. However, at the start of the last trimester, MAP began to rise further in the BPH/5 mice; it rose to peak levels just before delivery and returned to prepregnancy levels by 2 days after delivery. This was accompanied by late-gestational proteinuria and progressive glomerulosclerosis. No changes were observed in the C57BL/6 group except for a small decrease in MAP at mid gestation. The BPH/5 group delivered significantly smaller litters despite normal numbers of fetuses early in gestation, and longitudinal ultrasound studies documented fetal demise before the onset of hypertension and renal disease. This is the first report of an animal model that spontaneously develops a syndrome that bears close resemblance to preeclampsia, and it should have an impact on our understanding of the pathophysiology of this disorder. Key Words: hypertension, gestational Ⅲ blood pressure Ⅲ pregnancy Ⅲ proteinuria Ⅲ preeclampsia P reeclampsia, the most prevalent hypertensive disorder of pregnancy, is defined by the development of hypertension and proteinuria after the 20th week of pregnancy. It is thought to have an impact on 6% to 10% of pregnancies and is the leading cause of maternal mortality in Western countries. 1 A distinguishing feature of the disorder is its complete resolution after delivery of the fetus and placenta, the only known effective means to avoid cataclysmic progression to overt eclampsia. The necessity for urgent preterm delivery, along with progressive intrauterine growth restriction, implicates preeclampsia as a leading cause of perinatal morbidity and mortality. 2 The preeclampsia/eclampsia syndrome was described by ancient civilizations. Despite considerable research effort to date, we still understand very little about its etiology and pathophysiology, which are complex and multifactorial. 3 Clinical research is difficult because of the logistics of testing hypotheses related to pathogenesis or treatment in an urgent high-risk setting. Development of an animal model that fully recapitulates this complex ...
Transgenic mice were generated containing a 1542-base pair fragment of the kidney androgen-regulated protein (KAP) promoter fused to the human angiotensinogen (HAGT) gene with the goal of specifically targeting inducible expression of renin-angiotensin system components to the kidney. High level expression of both KAP-HAGT and endogenous KAP mRNA was evident in the kidney of male mice from two independent transgenic lines. Renal expression of the transgene in female mice was undetectable under basal conditions but could be strongly induced by administration of testosterone. Testosterone treatment did not cause a transcriptional induction in any other tissues examined. However, an analysis of six androgen target tissues in males revealed that the transgene was expressed in epididymis. No other extra-renal expression of the transgene was detected. In situ hybridization demonstrated that expression of HAGT (and KAP) mRNA in males and testosterone-treated females was restricted to proximal tubule epithelial cells in the renal cortex. Although there was no detectable human angiotensinogen protein in plasma, it was evident in the urine, consistent with a pathway of synthesis in proximal tubule cells and release into the tubular lumen. These results demonstrate that 1542 base pairs of the KAP promoter is sufficient to drive expression of a heterologous reporter gene in a tissue-specific, cell-specific, and androgen-regulated fashion in transgenic mice.The renin-angiotensin system (RAS) 1 is a classical endocrine system activated by the release of renin from the kidney and angiotensinogen (AGT) from the liver. In blood, renin proteolytically cleaves AGT to form angiotensin I (Ang-I) which is further processed by angiotensin converting enzyme to form Ang-II, a potent vasoconstrictor and antinatriuretic peptide. The RAS has been implicated in the genetic basis of hypertension and pre-eclampsia (1-4). Our understanding of the RAS in normal and pathophysiological regulation of blood pressure has been complicated by the fact that in addition to its actions as an endocrine system, certain individual tissues, such as the kidney (5-7), heart (8, 9), brain (10), and vasculature (11), contain all the components of the RAS cascade and therefore have the potential for local synthesis and action of Ang-II. In the kidney, for example, renin, AGT and ACE mRNAs, and proteins are synthesized in juxtaglomerular cells, proximal convoluted tubule (PCT) cells, and endothelial and tubular cells, respectively, and Ang-II type-1 (AT-1) and type-2 (AT-2) receptors are localized in glomeruli, collecting ducts, tubules, and vasa recta (12-18). The intrarenal RAS has been postulated to regulate various aspects of renal function including blood flow, natriuresis, and tubular-glomerular feedback, and may therefore participate in the pathogenesis of hypertension (19 -21). Our current understanding of the relative importance of the intrarenal versus systemic RAS comes largely from pharmacological studies (22) which have been limited by the specificity...
The present study was designed to determine ANG peptide content [ANG I, ANG II, ANG-(1-7)], ACE2 mRNA, and the immunocytochemical distribution of ANG-(1-7) and ACE2 in the uteroembryonic unit during early and late gestation in Sprague-Dawley rats and in a rat model of pregnancy-induced hypertension, the reduced uterine perfusion pressure (RUPP) model. At early pregnancy ANG-(1-7) and ACE2 staining were localized in the primary and secondary decidual zone and luminal and glandular epithelial cells. During late gestation, ANG-(1-7) and ACE2 staining was visualized in the labyrinth placenta and amniotic and yolk sac epithelium. Uterine ANG II concentration at early pregnancy was significantly decreased by 21-55% in the implantation and interimplantation sites compared with virgin rats, whereas ANG-(1-7) levels were maintained at prepregnancy levels. At late gestation, uterine concentrations of ANG I and ANG II were significantly increased (30% and 25%, respectively). In RUPP animals, ANG-(1-7) concentration is significantly reduced in the uterus (181 +/- 16 vs. 372 +/- 74 fmol/g of tissue) and placenta (143 +/- 26 vs. 197 +/- 20 fmol/g of tissue). ACE2 mRNA increased in the uterus of early pregnant compared with virgin rats, yet within the implantation site it was downregulated. At late pregnancy, ACE2 mRNA is elevated by 58% in the uterus and decreased by 59% in RUPP animals. The regulation of ANG-(1-7) and ACE2 in early and late pregnancy supports the hypothesis that ANG-(1-7) and ACE2 may act as a local autocrine/paracrine regulator throughout pregnancy, participating in the early (angiogenesis, apoptosis, and growth) and late (uteroplacental blood flow) events of pregnancy.
Pregnancy is a physiological condition characterized by a progressive increase of the different components of the renin-angiotensin system (RAS). The physiological consequences of the stimulated RAS in normal pregnancy are incompletely understood, and even less understood is the question of how this system may be altered and contribute to the hypertensive disorders of pregnancy. Findings from our group have provided novel insights into how the RAS may contribute to the physiological condition of pregnancy by showing that pregnancy increases the expression of both the vasodilator heptapeptide of the RAS, angiotensin-(1-7) [Ang-(1-7)], and of a newly cloned angiotensin converting enzyme (ACE) homolog, ACE2, that shows high catalytic efficiency for Ang II metabolism to Ang-(1-7). The discovery of ACE2 adds a new dimension to the complexity of the RAS by providing a new arm that may counter-regulate the activity of the vasoconstrictor component, while amplifying the vasodilator component. The studies reviewed in this article demonstrate that Ang-(1-7) increases in plasma and urine of normal pregnant women. In preeclamptic subjects we showed that plasma Ang-(1-7) was suppressed as compared to the levels found in normal pregnancy. In addition, kidney and urinary levels of Ang-(1-7) were increased in pregnant rats coinciding with the enhanced detection and expression of ACE2. These findings support the concept that in normal pregnancy enhanced ACE2 may counteract the elevation in tissue and circulating Ang II by increasing the rate of conversion to Ang-(1-7). These findings provide a basis for the physiological role of Ang-(1-7) and ACE2 during pregnancy.
Abstract-The chorionic villi in the placenta are responsible for the regulation of fetal oxygen and nutrient transport.Although the peripheral renin-angiotensin system is activated during normal pregnancy, the regulation of the local chorionic villi renin-angiotensin system remains unknown. Therefore, placental chorionic villous tissue was collected from nulliparous third-trimester normotensive or preeclamptic subjects and was analyzed for angiotensin peptide content, angiotensinogen, renin, angiotensin-converting enzyme (ACE), ACE2, neprilysin, angiotensin II type 1 (AT 1 ), angiotensin II type 2, Mas receptor mRNAs, and angiotensin receptor density and subtype. Angiotensin II in chorionic villi was significantly higher in preeclamptic subjects, whereas angiotensin (1-7) was not different. Key Words: preeclampsia Ⅲ renin angiotensin system Ⅲ pregnancy Ⅲ placenta Ⅲ angiotensin receptors Ⅲ Mas receptor Ⅲ angiotensin (1-7) P reeclampsia, a hypertensive disorder of pregnancy, is clinically defined as maternal hypertension, proteinuria, and generalized edema occurring after the 20th week of gestation. Preeclampsia is the second leading cause of maternal mortality in the United States, affecting 7% to 10% of all pregnancies and contributing significantly to stillbirths and neonatal morbidity and mortality. 1 Thus, the prevention of preeclampsia would have a significant impact on maternal and neonatal outcome. Nevertheless, the pathophysiology of preeclampsia remains poorly understood. Although preeclampsia is often considered a multisystem disorder, one of the postulated pathological features of this disease is an impaired maternal uterine spiral artery remodeling. In preeclampsia, there is a decrease of embryonic trophoblast cell invasion of the uterine spiral arteries, which, in turn, prevents the diameter of these arteries from expanding and consequently leads to a reduction of blood flow into the placenta. 2,3 Without the remodeling of the uterine vasculature, the placenta becomes hypoxic as gestation advances, resulting in an oxygen deficiency within the tissue. The hypoxic placenta can then release factors into the maternal circulation that result in generalized endothelial dysfunction, vascular inflammation, and proteinuria. [3][4][5] Although several factors, including soluble fms-like tyrosine kinase 1 6 and soluble endoglin, 7 were discovered recently to play a role in the pathogenesis of preeclampsia, there are still many unanswered questions in the development of this disease.The renin-angiotensin system (RAS) is an important regulator of blood pressure, sodium, and fluid homeostasis and has been shown previously to play a role in preeclampsia. In normal pregnancy, estrogen causes an overexpression of the RAS by increasing both tissue and circulating levels of angiotensinogen 8,9 and renin. 10 -13 Consequently, plasma angiotensin (Ang) II is increased in association with the rise of angiotensinogen and plasma renin activity during gestation. 14,15 Normal pregnant women are resistant to the pressor effects...
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