angiotensinogen and Hypoxia

To research the effects of gene polymorphisms of AGT at G-217A and T174M loci on incidence and the hypoxia acclimation to acute mountain sickness (AMS).. In step 1 the hypoxic exposure, for the G-217A locus in AGT, there was no significant difference between GG and GA+AA gene tester. While in step 2 the hypoxic exposure, the SpO. The G-217A may be the genetics sign of hypoxia acclimation. There is no obvious rel-evancy between the T174M polymorphism and the occurrence of AMS/hypoxia acclimation.

Topics: Acclimatization; Altitude Sickness; Angiotensinogen; Blood Pressure Monitoring, Ambulatory; Heart Rate; Humans; Hypoxia; Polymorphism, Genetic

Nitric oxide (NO) is an indispensible signalling molecule under hypoxic environment for both ethnic high altitude natives as well as lowland residents at high altitude. Several studies have reported higher levels of NO and bioactive NO products for both high altitude natives as well as healthy high altitude sojourners. But the metabolic pathways regulating the formation of NO and associated metabolites during hypoxia still remain elusive. In the present study, we profiled plasma proteomes of Ladakhi natives (3520 m) and lowland residents (post 1, 4 and 7 days stay) at the same altitude. This has resulted in the identification of 208 hypoxia responsive proteins (p < 0.05) and kininogen-plasma kallikrein-bradykinin as a major pathway regulating eNOS activity during hypoxia. In corroboration, we have also observed significant higher levels of plasma biomarkers for NO production (l-citrulline, nitrite, nitrate) for Ladakhi natives as compared to both lowland individuals healthy high altitude sojourners indicating higher NO availability. Since hypoxia-induced free radicals reduce NO availability, we also measured plasma levels of 8-isoprostanes, protein carbonyls and protein oxidation products in both Ladakhi natives and high altitude sojourners. Interestingly Ladakhi natives had significant lower levels of oxidative stress in comparison to high altitude sojourners but higher than lowland controls. These results suggest that plasma kallikrein-bradykinin-eNOS pathway along with moderate oxidative stress contributes to high altitude adaptation of Ladakhi natives.

Topics: Acclimatization; Adult; Altitude; Angiotensinogen; Arginine; Bradykinin; Citrulline; Humans; Hypoxia; Isoprostanes; Male; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type III; Nitrites; Oxidation-Reduction; Oxidative Stress; Plasma Kallikrein; Protein Carbonylation; Proteome; Signal Transduction

Ex-premature infants are at higher risk for hypertension and cardiovascular disease as adults, although the mechanisms underlying such increased risks are unknown. We hypothesize that postnatal exposure to intermittent hypoxia (IH) leads to cardiovascular dysfunction in adulthood with alterations of the renin-angiotensin pathway.. Neonatal mice were exposed to IH for 4 wk. At the age of 3 mo, various cardiovascular measurements were obtained.. IH-exposed mice exhibited higher systolic blood pressure, impaired baroreflex responses, and decreased heart rate variability. Furthermore, IH-exposed mice manifested evidence of endothelial dysfunction, as shown by reduced reperfusion indices after tail vessel occlusion and impaired vasodilatory responses to acetylcholine. CD31(+) endothelial cells isolated from mesenteric arteries of IH-exposed mice expressed higher levels of angiotensin-converting enzyme and reactive oxygen species; plasma angiotensin-II levels were also significantly higher in these animals. In addition, DNA methylation patterns of the Ace1 and the Agt genes in these cells were congruent with their expression patterns.. Our results suggest that exposures to postnatal IH alter the normal development of the renin-angiotensin system and promote the occurrence of cardiovascular dysfunction during adulthood in mice.

Topics: Age Factors; Angiotensin II; Angiotensinogen; Animals; Animals, Newborn; Baroreflex; Blood Pressure; Cardiovascular Diseases; DNA Methylation; Heart Rate; Hypoxia; Mice; Mice, Inbred C57BL; Renin-Angiotensin System

The carotid body (CB) plays an important role in the alteration of cardiorespiratory activity in chronic intermittent hypoxia (IH) associated with sleep-disordered breathing, which may be mediated by local expression of the renin-angiotensin system (RAS). We hypothesized a pathogenic role for IH-induced RAS expression in the CB. The CB expression of RAS components was examined in rats exposed to IH resembling a severe sleep-apnoeic condition for 7 days. In situ hybridization showed an elevated expression of angiotensinogen in the CB glomus cells in the hypoxic group when compared with the normoxic control group. Immunohistochemical studies and Western blot analysis revealed increases in the protein level of both angiotensinogen and angiotensin II type 1 (AT1) receptors in the hypoxic group, which were localized to the glomic clusters containing tyrosine hydroxylase. RT-PCR studies confirmed that levels of the mRNA expression of angiotensinogen, angiotensin-converting enzyme, AT1a and AT2 receptors were significantly increased in the CBs of the hypoxic rats. Functionally, the [Ca(2+)]i response to exogenous angiotensin II was enhanced in fura-2-loaded glomus cells dissociated from hypoxic rats when compared with those of the normoxic control animals. Pretreatment with losartan, but not PD123319, abolished the angiotensin II-induced [Ca(2+)]i response, suggesting an involvement of AT1 receptors. Moreover, daily treatment of the IH group of rats with losartan attenuated the levels of oxidative stress, gp91(phox) expression and macrophage infiltration in the CB. Collectively, the upregulated local RAS expression could play a pathogenic role in the augmented CB activity and local inflammation via AT1 receptor activation during IH conditions in patients with sleep-disordered breathing.

Topics: Angiotensin II; Angiotensinogen; Animals; Calcium; Carotid Body; Fura-2; Hypoxia; Male; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Sleep Apnea Syndromes; Tyrosine 3-Monooxygenase; Up-Regulation

Antenatal maternal hypoxia (AMH) can lead to intrauterine growth restriction (IUGR), as well as idiopathic pulmonary hypertension of newborn and adult, the latter of which may be a consequence of alterations in the local pulmonary renin-angiotensin system (RAS). Little is known of these adaptations, however. Thus, we tested the hypothesis that antenatal maternal hypoxia is associated with alterations in gene and protein expression of the pulmonary renin-angiotensin system, which may play an important role in pulmonary disorders in the offspring. In FVB/NJ mice, we studied messenger RNA (mRNA) and protein expression, as well as promoter DNA methylation and microRNA (miRNA) levels in response to 48 hours hypoxia (10.5% O(2)) at 15.5 day post coitum (DPC). In response to AMH, the pulmonary mRNA levels of angiotensin-converting enzyme (ACE) 1.2, ACE-2, and angiotensin II type 1b (AT-1b) receptors were increased significantly, as compared to controls (N = 4). In response to antenatal hypoxia, pulmonary protein levels of renin and ACE-2 also were increased significantly, whereas ACE-1 protein expression was reduced. In fetal lungs, we also observed reduced expression of the miRNAs: mmu-mir -199b, -27b, -200b, and -468 that putatively increase the translation of renin, ACE-1, ACE-2, and AT-1 receptors, respectively. In response to AMH, promoter methylation of ACE was unchanged. We conclude that AMH leads to changes in expression of pulmonary RAS of fetal mice. The possible implications of these changes for the regulation of pulmonary vascular contractility in later life remain to be explored.

Topics: Adaptation, Physiological; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Regulation; Hypoxia; Lung; Male; Mice; Mice, Inbred Strains; Peptidyl-Dipeptidase A; Pregnancy; Prenatal Exposure Delayed Effects; Pulmonary Circulation; Renin; Renin-Angiotensin System; Stress, Physiological; Vasoconstriction

The present study aimed to investigate the effects of olmesartan, an antagonist for angiotensin II receptor type 1(AT1), on the activation of extracellular signal-regulated kinases (ERK)1/2, tissue remodeling, and pro-inflammatory signals in the right ventricle and lung of mice during the early phase of hypobaric hypoxia. Phosphorylation of ERK1/2 in both tissue types in response to hypoxia peaked at 1-3 days, and declined rapidly in the right ventricle, whereas in the lung it was sustained for at least 8 days. Upregulation of angiotensinogen mRNA was observed in the hypoxic lung at 4-9 days, but not in the hypoxic right ventricle and pulmonary artery. Olmesartan inhibited the hypoxia-induced phosphorylation of ERK1/2 in the lung, but not in the right ventricle. Neither right ventricular hypertrophy nor the thickening of the intrapulmonary arterial wall was ameliorated by olmesartan. However, this drug inhibited the expression of the mRNA for angiotensinogen and several pro-inflammatory factors, including interleukin-6 and inducible nitric oxide synthase in the hypoxic lung. These results suggest that olmesartan blocks a potential positive feedback loop of the angiotensin II-AT1 receptor system, which may lead to attenuate pro-inflammatory signals in the mouse lung, that are associated with hypoxic pulmonary hypertension, without inducing any appreciable effects on the compensatory cardiopulmonary hypertrophy at an early phase of exposure to a hypobaric hypoxic environment.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Gene Expression Regulation; Heart Ventricles; Hypertension, Pulmonary; Hypoxia; Imidazoles; Inflammation Mediators; Lung; Male; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Olmesartan Medoxomil; Phosphorylation; Pulmonary Artery; RNA, Messenger; Tetrazoles; Up-Regulation

Evidence exists for the presence of a functional angiotensin system in the carotid body, which can modulate the excitability of the carotid body chemoreceptors. In the present study, the effect of chronic hypoxia on the expression and localization of the angiotensinogen (AGT) and angiotensin-converting enzyme (ACE), the two critical components of an intrinsic angiotensin-generating system in the rat carotid body, are investigated by in situ hybridization histochemistry, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. In situ hybridization showed that the messenger RNA (mRNA) expression of AGT was localized within the type-I glomus cells of the carotid body, which was subjected to be upregulated under the stress of chronic hypoxia. RT-PCR further confirmed a significant increase in the expression of AGT mRNA by chronic hypoxia. Consistently, Western blot analysis demonstrated that chronic hypoxia could elicit the upregulation of AGT protein in chronically hypoxic carotid bodies when compared with their normoxic controls. On the other hand, there was a slight but significant increase in ACE mRNA expression during chronic hypoxia. This study suggests that chronic hypoxia can activate a local angiotensin-generating system in the carotid body, notably its obligatory component AGT. The activation of such an intrinsic, angiotensin-generating system in the carotid body during chronic hypoxia should be important in the modulation of cardiopulmonary adaptation in the hypoxic ventilatory response and the electrolyte as well as water homeostasis.

Topics: Adaptation, Physiological; Angiotensinogen; Angiotensins; Animals; Carotid Body; Chemoreceptor Cells; Chronic Disease; Hypoxia; Male; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; RNA, Messenger; Up-Regulation

The circulating renin-angiotensin system (RAS) plays a crucial role in the regulation of blood pressure, electrolytes, and fluid homeostasis. In contrast to the circulating RAS, the presence of an intrinsic RAS has been demonstrated in different tissues/organs, which may affect both local and global functions of a biologic system. Our previous studies provided solid evidence of the existence of a local RAS in rat pancreas. Our further investigation showed that such a pancreatic RAS could be activated by experimental models of chronic hypoxia and chemically induced pancreatitis. These previous findings formed the basis for the current study.. Adult Sprague-Dawley rats were exposed to isobaric hypoxia (10% O2), and the effects on the circulating and pancreatic RAS were documented.. The current study shows that exposure of rats to isobaric hypoxia caused a time-dependent increase in plasma renin activity. The activation of circulating RAS by hypoxia was associated with a parallel upregulation of local RAS components, including the mRNA expression of angiotensinogen and angiotensin II receptor types I and II in the pancreas.. The upregulation of local pancreatic RAS, along with its counterpart circulating RAS, may be responsible for both physiologic and pathophysiologic aspects of a biologic system under chronic hypoxic stress.

Topics: Angiotensinogen; Animals; Chronic Disease; Hypoxia; Kinetics; Pancreas; Rats; Rats, Sprague-Dawley; Receptors, Angiotensin; Renin; Renin-Angiotensin System; RNA, Messenger; Up-Regulation

The presence of an intrinsic renin-angiotensin system (RAS) in the rat epididymis has been previously established by showing the expression of several key RAS components, and in particular angiotensinogen, the indispensable element for the intracellular generation of angiotensin II. In this study, the possible involvement of this local epididymal RAS in the testicular effects of chronic hypoxia was investigated. Semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR), Western blotting and by in situ hybridization histochemistry of the rat epididymis were used to show changes in localization and expression of angiotensinogen. Results from RT-PCR analysis demonstrated that chronic hypoxia caused a marked decrease (60%) in the expression of angiotensinogen mRNA, when compared with that in the normoxic epididymis. Western blot analysis demonstrated a less decrease (35%) in the expression of angiotensinogen protein. In situ hybridization histochemistry showed that the reduced angiotensinogen mRNA in chronic hypoxia was specifically localized to the epididymal epithelium from the cauda, corpus and caput regions of the epididymis; a distribution similar to that of normoxic rats. It was concluded that chronic hypoxia decreases the transcriptional and translational expression of angiotensinogen, and thus local formation of angiotensin II, in the rat epididymis.

Topics: Angiotensin II; Angiotensinogen; Animals; Blotting, Western; Chronic Disease; Down-Regulation; Epididymis; Hypoxia; In Situ Hybridization; Male; Oligonucleotides, Antisense; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Previous studies have provided evidence that several key elements of renin-angiotensin system (RAS) are present in the rat pancreas, notably angiotensinogen, which is mandatory for intracellular generation of physiologically active angiotensin II. The data support the existence of an intrinsic RAS, which may be important for pancreatic blood flow and ductal anion secretion. In the present study, the effect of chronic hypoxia on the expression of RAS components, particularly at the levels of its precursor angiotensinogen and its receptor subtypes AT(1) and AT(2), were investigated in the rat pancreas. Results from western blot and semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) analyses unequivocally showed that chronic hypoxia caused a marked increase in angiotensinogen both at the protein and gene levels when compared with that in the normoxic pancreas. However, results from RT-PCR showed that there was a differential effect of chronic hypoxia on the expression of AT(1) and AT(2) receptor subtypes, which exhibited subtype-specific changes in gene expression. For AT(1), chronic hypoxia did not cause a significant change in mRNA expression for AT(1a) but a significant increase in mRNA expression for AT(1b). For AT(2), chronic hypoxia caused a marked increase in its mRNA expression. The increased expression of RAS component genes by chronic hypoxia and its significance of changes may be important for physiological and pathophysiological aspects of the pancreas.

Topics: Angiotensinogen; Animals; Animals, Newborn; Chronic Disease; Hypoxia; Pancreas; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The aim of the present study was to provide an overview of the role of circulating gonadal steroids on the adaptive changes of the renin-angiotensin system to chronic hypobaric hypoxia (CHH: 4400 m simulated altitude in an hypobaric chamber) and the development of experimental hypertension by bilateral renal ischemia. In order to fulfill this goal, blood pressure (BP), plasma renin activity (PRA) and plasma angiotensinogen concentration (PAoC) as well as haematocrit (Htc) and body weight (BW) of intact and post-puberal castrated normotensive (Nt) and hypertensive (Ht) rats of both sexes were studied following an experimental design similar to that of previous works. Post-puberal castration decreased BP of Nt and Ht rats subjected to CHH. Sexual dimorphism in BP, PRA and PAoC was maintained while that in haematocrit disappeared after castration. Results suggest that circulating sexual steroid hormones are involved in the response of the renin-angiotensin system to the experimental conditions of environmental reduced O2 partial pressure.

Topics: Adaptation, Physiological; Altitude; Angiotensinogen; Animals; Blood Pressure; Body Weight; Female; Gonadal Steroid Hormones; Hematocrit; Hypertension, Renovascular; Hypoxia; Male; Orchiectomy; Ovariectomy; Rats; Rats, Wistar; Renin; Renin-Angiotensin System

Concentrations of plasma renin (PRC) and plasma renin substrate (PRS) were measured during the first week of life in 52 infants born at less than 37 weeks' gestation (mean (SEM) gestation 30 (0.4) weeks, mean (SEM) birth weight 1.35 (0.08) kg). Both PRC (median 35, interquartiles 16.3, 94.5 ng/ml/hour) and PRS (median 2.3, interquartiles 1.3, 5.0 micrograms/ml) were raised compared with adults. The proportional rise in PRC was much greater than that in PRS, suggesting that PRS may be rate limiting in the generation of angiotensin I. Log10 PRC was inversely proportional to gestational age and a high urinary sodium loss was associated with a significantly raised log10 PRC. In hypoxaemic infants, there was a strong correlation between log10 PRS and haemoglobin concentration; this is a new observation in human infants but consistent with data available from other species.

Topics: Angiotensinogen; Female; Gestational Age; Humans; Hypoxia; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Renin; Renin-Angiotensin System; Sodium

When rats are subjected to hypoxia, an increase in serum angiotensinogen concentration occurs which is accompanied by the appearance of serum erythropoietin (EP) during the first 24 h. Subsequent increases in EP reach maximum values 24 to 48 h after increases in packed cell volume (PCV) and serum renin levels. The current experiments were designed to determine if a decrease in iron stores is the stimulus for renin production when rats are rapidly expanding their red cell volume in a hypoxic environment. Young rats fed McCall's low iron diet were paired with rats fed the same diet supplemented with ferric citrate (6 g/kg diet). After two weeks at ambient pressure, they were subjected to hypoxia (0.48 atm) for 1 to 10 days. After 5 days at the reduced pressure, a fraction of the rats on the low iron diet were fed the iron-supplemented diet. At the time of sacrifice, serum was assayed for total iron binding capacity (TIBC) and renin. Rats that were fed the low iron diet showed an increase in TIBC, an increase in serum renin and a positive correlation between serum renin and TIBC. Rats that were fed a normal iron diet under the same conditions had lower TIBC, lower serum renin and no correlation between serum renin and TIBC. When low iron diet rats were supplemented with iron, TIBC and serum renin decreased. These experiments may have a clinical counterpart. The total iron binding capacity, renin and angiotensinogen were measured in the serum of women during the first 19 weeks of pregnancy. Women during early pregnancy showed an increase in TIBC, an increase of renin and angiotensinogen in the serum and a positive correlation between TIBC and renin concentration. It is suggested that the increased concentration of renin in the serum of women during the first 19 weeks of pregnancy and in the serum of rats that are rapidly expanding their red cell volume are related to a decrease in iron stores.

Topics: Angiotensinogen; Animals; Atmospheric Pressure; Carrier Proteins; Erythrocyte Count; Female; Humans; Hypoxia; Iron; Iron Deficiencies; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Rats; Renin