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1.  Angiotensin II type I receptor gene polymorphism: anthropometric and metabolic syndrome traits 
Journal of Medical Genetics  2005;42(5):396-401.
Background: The renin angiotensin system is important in the regulation of vascular tone and fluid and electrolyte balance. The angiotensin converting enzyme gene (ACE) genotype has been shown to affect exercise response and glucose load response dependent on birth weight. Angiotensin II type I receptor (AGTR1) A1166C has previously been associated with the development of hypertension and coronary disease, but its metabolic effects have not been investigated.
Method: AGTR1 A1166C was genotyped by allele specific PCR in 378 individuals from Hertfordshire, UK, who had been characterised for metabolic syndrome traits.
Results: Genotype counts were: AA, 183; AC, 170; CC, 25, consistent with Hardy-Weinberg equilibrium. The CC genotype was associated with significantly lower body mass index (by 1.7 units) in men (p = 0.03), and the same magnitude effect in women with significant lower weight in both genders (p = 0.01), also lower waist circumference and waist-hip ratio (p = 0.01) in men, with a trend for lower waist circumference in women also. Additionally, the CC genotype and/or C allele was associated with lower fasting glucose and insulin, and 30 and 120 min glucose in men (respectively, p = 0.08, 0.04, 0.01, 0.06). Lower means of systolic blood pressure, pulse pressure, cholesterol, and fasting triglyceride were also observed for the CC genotype in both genders though these were not statistically significant.
Conclusions: The AGTR1 1166 CC genotype appears to predispose to favourable anthropometric and metabolic traits, relative to cardiovascular risk.
doi:10.1136/jmg.2004.026716
PMCID: PMC1736059  PMID: 15863668
2.  New insights into angiotensin receptor actions: from blood pressure to aging 
Purpose of the review
The renin-angiotensin system (RAS) is critical for cardiovascular control, impacting normal physiology and disease pathogenesis. Although several biologically active peptides are generated by this system, its major actions are mediated by angiotensin II acting through its type 1 (AT1) and type 2 (AT2) receptors. Along with their effects to influence blood pressure and hemodynamics, recent studies have provided evidence that angiotensin receptors influence a range of processes independent from hemodynamic effects.
Recent findings
This review is focused on new molecular mechanisms underlying actions of AT1 receptors to influence vasoconstriction, inflammation, immune responses, and longevity. Moreover, we also highlight new advances in understanding functions of the AT2 receptor in end-organ damage, emphasizing the AT2 receptor as a potential therapeutic target in cardiovascular diseases.
Summary
Here we review recent advances in understanding the role of angiotensin receptors in normal physiology and disease states, focusing on their properties that may contribute to blood pressure regulation, end-organ damage, autoimmune disease and longevity.
doi:10.1097/MNH.0b013e3283414d40
PMCID: PMC3087382  PMID: 21076298
Angiotensin receptors; hypertension; aging; vascular function; immunity
3.  The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction 
An association has been shown between plasma renin activity (PRA) and the risk of cardiovascular disease. There is also evidence that angiotensin II exerts detrimental effects on progression and instabilization of atherosclerotic plaque. The renin-angiotensin system (RAS) can be inhibited through inhibition of angiotensin I (Ang I) generation from angiotensinogen by direct renin inhibitors, inhibition of angiotensin II (Ang II) generation from angiotensin I by angiotensin-converting enzyme inhibitors and finally by direct inhibition of the action of Ang II receptor level. Aliskiren, the first direct renin inhibitor to reach the market, is a low-molecular-weight, orally active, hydrophilic nonpeptide. Aliskiren blocks Ang I generation, while plasma renin concentration increases because the drugs blocks the negative feed-back exerted by Ang II on renin synthesis. Because of its long pharmacological half-life, aliskiren is suitable for once-daily administration. Its through-to-peak ratio approximates 98% for the 300 mg/day dose. Because of its mechanism of action, aliskiren might offer the additional opportunity to inhibit progression of atherosclerosis at tissue level. Hypertension is an approved indication for this drug, which is also promising for the treatment of heart failure. The efficacy of this drug in reducing major clinical events is being tested in large ongoing clinical trials.
PMCID: PMC2605336  PMID: 19183745
plasma renin activity; renin angiotensin system; aliskiren; angiotensinogen; renin; hypertension; heart failure; diabetes
4.  Expression of renin–angiotensin system components in the early bovine embryo 
Endocrine Connections  2012;1(1):22-30.
The renin–angiotensin system (RAS), mainly associated with the regulation of blood pressure, has been recently investigated in female reproductive organs and the developing foetus. Angiotensin II (Ang II) influences oviductal gamete movements and foetal development, but there is no information about RAS in the early embryo. The aim of this study was to determine whether RAS components are present in the pre-implantation embryo, to determine how early they are expressed and to investigate their putative role at this stage of development. Bovine embryos produced in vitro were used for analysis of RAS transcripts (RT-PCR) and localisation of the receptors AGTR1 and AGTR2 (immunofluorescent labelling). We also investigated the effects of Ang II, Olmesartan (AGTR1 antagonist) and PD123319 (AGTR2 antagonist) on oocyte cleavage, embryo expansion and hatching. Pre-implanted embryos possessed AGTR1 and AGTR2 but not the other RAS components. Both receptors were present in the trophectoderm and in the inner cell mass of the blastocyst. AGTR1 was mainly localised in granular-like structures in the cytoplasm, suggesting its internalisation into clathrin-coated vesicles, and AGTR2 was found mainly in the nuclear membrane and in the mitotic spindle of dividing trophoblastic cells. Treating embryos with PD123319 increased the proportion of hatched embryos compared with the control. These results, the first on RAS in the early embryo, suggest that the pre-implanted embryo responds to Ang II from the mother rather than from the embryo itself. This may be a route by which the maternal RAS influences blastocyst hatching and early embryonic development.
doi:10.1530/EC-12-0013
PMCID: PMC3681317  PMID: 23781300
angiotensin II; embryo; development; receptor
5.  Activation of Local Chorionic Villi Angiotensin II Levels But Not Angiotensin (1–7) in Preeclampsia 
Hypertension  2008;51(4):1066-1072.
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 (AT1), 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. Angiotensinogen and AT1 receptor gene expression was significantly higher in preeclamptic subjects. No differences were observed in renin, ACE, ACE2, or neprilysin gene expression. Mas receptor mRNA in preeclamptic subjects was decreased. The AT1 receptor was the predominant receptor subtype in normal and preeclamptic chorionic villi. There was no difference in the density of the AT1, angiotensin II type 2, and angiotensin (1–7) receptors. These results indicate that enhanced chorionic villous expression of angiotensin II may result from increased angiotensinogen. Elevated angiotensin II, acting through the AT1 receptor, may favor vasoconstriction in placental chorionic villi and contribute to impaired fetal blood flow and decreased fetal nutrition observed during preeclampsia.
doi:10.1161/HYPERTENSIONAHA.107.103861
PMCID: PMC2705753  PMID: 18259034
preeclampsia; renin angiotensin system; pregnancy; placenta; angiotensin receptors; Mas receptor; angiotensin (1–7)
6.  Angiotensin II Activates the Calcineurin/NFAT Signaling Pathway and Induces Cyclooxygenase-2 Expression in Rat Endometrial Stromal Cells 
PLoS ONE  2012;7(5):e37750.
Cyclooxygenase (COX)-2, the inducible isoform of cyclooxygenase, plays a role in the process of uterine decidualization and blastocyst attachment. On the other hand, overexpression of COX-2 is involved in the proliferation of the endometrial tissue during endometriosis. Deregulation of the renin-angiotensin-system plays a role in the pathophysiology of endometriosis and pre-eclampsia. Angiotensin II increases intracellular Ca2+ concentration by targeting phospholypase C-gamma in endometrial stromal cells (ESC). A key element of the cellular response to Ca2+ signals is the activity of the Ca2+- and calmodulin-dependent phosphatase calcineurin. Our first aim was to study whether angiotensin II stimulated Cox-2 gene expression in rat ESC and to analyze whether calcineurin activity was involved. In cells isolated from non-pregnant uteri, COX-2 expression -both mRNA and protein- was induced by co-stimulation with phorbol ester and calcium ionophore (PIo), as well as by angiotensin II. Pretreatment with the calcineurin inhibitor cyclosporin A inhibited this induction. We further analyzed the role of the calcineurin/NFAT signaling pathway in the induction of Cox-2 gene expression in non-pregnant rat ESC. Cyclosporin A abolished NFATc1 dephosphorylation and translocation to the nucleus. Cyclosporin A also inhibited the transcriptional activity driven by the Cox-2 promoter. Exogenous expression of the peptide VIVIT -specific inhibitor of calcineurin/NFAT binding- blocked the activation of Cox-2 promoter and the up-regulation of COX-2 protein in these cells. Finally we analyzed Cox-2 gene expression in ESC of early-pregnant rats. COX-2 expression -both mRNA and protein- was induced by stimulation with PIo as well as by angiotensin II. This induction appears to be calcineurin independent, since it was not abrogated by cyclosporin A. In conclusion, angiotensin II induced Cox-2 gene expression by activating the calcineurin/NFAT signaling pathway in endometrial stromal cells of non-pregnant but not of early-pregnant rats. These results might be related to differential roles that COX-2 plays in the endometrium.
doi:10.1371/journal.pone.0037750
PMCID: PMC3360626  PMID: 22662209
7.  Divergent functions of angiotensin II receptor isoforms in the brain 
Journal of Clinical Investigation  2000;106(1):103-106.
The renin-angiotensin system (RAS) plays a critical role in cardiovascular and fluid homeostasis. The major biologically active peptide of the RAS is angiotensin II, which acts through G protein–coupled receptors of two pharmacological classes, AT1 and AT2. AT1 receptors, expressed in brain and peripheral tissues, mediate most classically recognized actions of the RAS, including blood pressure homeostasis and regulation of drinking and water balance. In rodents, two highly homologous AT1 receptor isoforms, termed AT1A and AT1B receptors, are expressed at different levels in major forebrain cardiovascular and fluid regulatory centers, with AT1A expression generally exceeding AT1B expression, but the relative contributions of these receptor subtypes to central angiotensin II responses are not known. We used gene targeting in combination with a unique system for maintaining catheters in the cerebral ventricles of conscious mice to test whether there are differential roles for AT1A and AT1B receptors in responses elicited by angiotensin II in the brain. Here we show that the blood pressure increase elicited by centrally administered angiotensin II can be selectively ascribed to the AT1A receptor. However, the drinking response requires the presence of AT1B receptors. To our knowledge, this is the first demonstration of a primary and nonredundant physiological function for AT1B receptors.
PMCID: PMC314366  PMID: 10880053
8.  Disruption of the Ang II type 1 receptor promotes longevity in mice 
The renin-angiotensin system plays a role in the etiology of hypertension and the pathophysiology of cardiac and renal diseases in humans. Ang II is the central product of this system and is involved in regulating immune responses, inflammation, cell growth, and proliferation by acting through Ang II type 1 receptors (AT1 and AT2). Here, we show that targeted disruption of the Agtr1a gene that encodes AT1A results in marked prolongation of life span in mice. Agtr1a–/– mice developed less cardiac and vascular injury, and multiple organs from these mice displayed less oxidative damage than wild-type mice. The longevity phenotype was associated with an increased number of mitochondria and upregulation of the prosurvival genes nicotinamide phosphoribosyltransferase (Nampt) and sirtuin 3 (Sirt3) in the kidney. In cultured tubular epithelial cells, Ang II downregulated Sirt3 mRNA, and this effect was inhibited by an AT1 antagonist. These results demonstrate that disruption of AT1 promotes longevity in mice, possibly through the attenuation of oxidative stress and overexpression of prosurvival genes, and suggests that the Ang II/AT1 pathway may be targeted to influence life span in mammals.
doi:10.1172/JCI36703
PMCID: PMC2648681  PMID: 19197138
9.  Cognitive-enhancing effects of angiotensin IV 
BMC Neuroscience  2008;9(Suppl 2):S15.
Angiotensin IV is a derivative of the potent vasoconstrictor angiotensin II and it has been shown to enhance acquisition, consolidation and recall in animal models of learning and memory when administered centrally or peripherally. Whether changes in angiotensin IV activity underlie the cognitive effects of those cardiovascular drugs designed to disrupt the peripheral renin-angiotensin system in humans remains undetermined, but angiotensin IV appears to be a worthy candidate for consideration in drug development programmes. The mechanism of action of angiotensin IV is still debated, although its AT4 receptor has been convincingly identified as being insulin-regulated amino peptidase, which is also known as oxytocinase and placental leucine aminopeptidase. It is speculated that angiotensin IV may interact with insulin-regulated amino peptidase to enhance neuronal glucose uptake, prevent metabolism of other neuroactive peptides, induce changes in extracellular matrix molecules, or induce release of acetylcholine and/or dopamine. All of these things may be responsible for the beneficial effects on cognition, but none of them are yet proven. Importantly, strain differences in murine responses to angiotensin IV suggest that some individuals may benefit from drugs targeted to the AT4 receptor whilst others may be refractory. At present it thus appears that those individuals with the poorest baseline cognition may receive greatest benefit, but possible genetic differences in responses to angiotensin IV cannot be ruled-out.
doi:10.1186/1471-2202-9-S2-S15
PMCID: PMC2604899  PMID: 19090988
10.  Intratubular Renin-Angiotensin System in Hypertension 
Current hypertension reviews  2006;2(2):151-157.
It is well recognized that the renin-angiotensin system plays an important role in the regulation of arterial pressure and sodium homeostasis. Recent years, many studies have shown that local tissue angiotensin II levels are differentially regulated and cannot be explained on the basis of circulating concentrations. All of the components needed for angiotensin II generation are present within the various compartments in the kidney including the renal interstitium and the tubular network. The cascade of the renin-angiotensin system demonstrates three major possible sites for the pharmacological interruption of the renin-angiotensin system: the interaction of renin with its substrate, angiotensinogen, the angiotensin converting enzyme, and angiotensin II type 1 receptors. This brief article will focus on the role of the intratubular renin-angiotensin system in the pathophysiology of hypertension and the responses to the renin-angiotensin system blockade by renin inhibitors, angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockers.
doi:10.2174/157340206776877325
PMCID: PMC2752977  PMID: 19789728
Renin-angiotensin system; hypertension; kidney; angiotensin converting enzyme inhibitors; angiotensin II type 1 receptor blockers
11.  Systemic candesartan reduces brain angiotensin II via downregulation of brain renin–angiotensin system 
The renin–angiotensin system has an important function in the regulation of blood pressure as well as in pathophysiological processes in the central nervous system. We examined the effects of the angiotensin receptor blocker candesartan (10 mg kg−1 per day, p.o.) on brain angiotensin II levels in angiotensin II-infused hypertensive rats. Angiotensin II or vehicle was infused subcutaneously for 14 days in Sprague–Dawley rats. Angiotensin II infusion resulted in increased blood pressure, an effect that was blocked by candesartan treatment. There was no effect of the angiotensin II infusion on Angiotensin II levels in the brain or on blood–brain barrier permeability. Brain tissue angiotensinogen and angiotensin converting enzyme mRNA levels were not changed by angiotensin II infusion but were decreased by candesartan treatment. At 2 weeks of treatment, CV11974, an active form of candesartan, was detectable in the plasma but was not detectable in brain tissue. These data suggest that treatment with candesartan decreases brain angiotensin II by decreasing brain angiotensinogen and angiotensin converting enzyme gene expression.
doi:10.1038/hr.2009.200
PMCID: PMC2818705  PMID: 19942928
angiotensin II; AT1 type 1 receptor; brain; candesartan
12.  Renin-angiotensin-aldosterone system and glucose homeostasis 
Trends in pharmacological sciences  2011;32(12):734-739.
The renin-angiotensin-aldosterone system is inappropriately activated in obesity. In individuals at risk for diabetes, inhibition of the renin-angiotensin-aldosterone system protects against kidney and heart disease, and also reduces the incidence of diabetes in large clinical trials. At a cellular level, angiotensin II and aldosterone induce insulin resistance by increasing oxidative stress and altering insulin signaling, leading to decreased glucose transport. Angiotensin II also contributes to oxidative stress, inflammation, and apoptosis in pancreatic β-cells. Aldosterone diminishes glucose-stimulated insulin secretion in vivo and in vitro from isolated pancreatic islets and cultured β-cells through a mineralocorticoid receptor-independent mechanism. We review these findings in the context of pharmacological strategies to interrupt the renin-angiotensin-aldosterone system to highlight the potential application of these strategies to the prevention of diabetes progression.
doi:10.1016/j.tips.2011.07.006
PMCID: PMC3223326  PMID: 21880378
13.  Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system 
Journal of Clinical Investigation  2005;115(4):1092-1099.
Angiotensin II, acting through type 1 angiotensin (AT1) receptors, has potent effects that alter renal excretory mechanisms. Control of sodium excretion by the kidney has been suggested to be the critical mechanism for blood pressure regulation by the renin-angiotensin system (RAS). However, since AT1 receptors are ubiquitously expressed, precisely dissecting their physiological actions in individual tissue compartments including the kidney with conventional pharmacological or gene targeting experiments has been difficult. Here, we used a cross-transplantation strategy and AT1A receptor–deficient mice to demonstrate distinct and virtually equivalent contributions of AT1 receptor actions in the kidney and in extrarenal tissues to determining the level of blood pressure. We demonstrate that regulation of blood pressure by extrarenal AT1A receptors cannot be explained by altered aldosterone generation, which suggests that AT1 receptor actions in systemic tissues such as the vascular and/or the central nervous systems make nonredundant contributions to blood pressure regulation. We also show that interruption of the AT1 receptor–mediated short-loop feedback in the kidney is not sufficient to explain the marked stimulation of renin production induced by global AT1 receptor deficiency or by receptor blockade. Instead, the renin response seems to be primarily determined by renal baroreceptor mechanisms triggered by reduced blood pressure. Thus, the regulation of blood pressure by the RAS is mediated by AT1 receptors both within and outside the kidney.
doi:10.1172/JCI200523378
PMCID: PMC1070417  PMID: 15841186
14.  Contributions of Renin-Angiotensin System-Related Gene Interactions to Obesity in a Chinese Population 
PLoS ONE  2012;7(8):e42881.
Background
Gene-gene interactions may be partly responsible for complex traits such as obesity. Increasing evidence suggests that the renin-angiotensin system (RAS) contributes to the etiology of obesity. How the epistasis of genes in the RAS contributes to obesity is still under research. We aim to evaluate the contribution of RAS-related gene interactions to a predisposition of obesity in a Chinese population.
Methodology and Principal Findings
We selected six single nucleotide polymorphisms (SNPs) located in angiotensin (AGT), angiotensin converting enzyme (ACE), angiotensin type 1 receptor (AGTR1), MAS1, nitric oxide synthase 3 (NOS3) and the bradykinin B2 receptor gene (BDKRB2), and genotyped them in 324 unrelated individuals with obesity (BMI ≥28 kg/m2) and 373 non-obese controls (BMI 18.5 to <24 kg/m2) from a large scale population-based cohort. We analyzed gene-gene interactions among 6 polymorphic loci using the Generalized Multifactor Dimensionality Reduction (GMDR) method, which has been shown to be effective for detecting gene-gene interactions in case-control studies with relatively small samples. Then we used logistic regression models to confirm the best combination of loci identified in the GMDR. It showed a significant gene-gene interaction between the rs220721 polymorphism in the MAS1 gene and the rs1799722 polymorphism in the gene BDKB2R. The best two-locus combination scored 9 for cross-validation consistency and 9 for sign test (p = 0.0107). This interaction showed the maximum consistency and minimum prediction error among all gene-gene interaction models evaluated. Moreover, the combination of the MAS1 rs220721 and the BDKRB2 rs1799722 was associated with a significantly increased risk of obesity (OR 1.82, CI 95%: 1.15–2.88, p = 0.0103).
Conclusions and Significance
These results suggest that the SNPs from the RAS-related genes may contribute to the risk of obesity in an interactive manner in a Chinese population. The gene-gene interaction may serve as a novel area for obesity research.
doi:10.1371/journal.pone.0042881
PMCID: PMC3412812  PMID: 22880127
15.  ACE2-Ang-(1-7)-Mas Axis in Brain: A Potential Target for Prevention and Treatment of Ischemic Stroke 
Current Neuropharmacology  2013;11(2):209-217.
The renin-angiotensin system (RAS) in brain is a crucial regulator for physiological homeostasis and diseases of cerebrovascular system, such as ischemic stroke. Overactivation of brain Angiotensin-converting enzyme (ACE) - Angiotensin II (Ang II) - Angiotensin II type 1 receptor (AT1R) axis was found to be involved in the progress of hypertension, atherosclerosis and thrombogenesis, which increased the susceptibility to ischemic stroke. Besides, brain Ang II levels have been revealed to be increased in ischemic tissues after stroke, and contribute to neural damage through elevating oxidative stress levels and inducing inflammatory response in the ischemic hemisphere via AT1R. In recent years, new components of RAS have been discovered, including ACE2, Angiotensin-(1–7) [Ang-(1-7)] and Mas, which constitute ACE2-Ang-(1-7)-Mas axis. ACE2 converts Ang II to Ang-(1-7), and Ang-(1-7) binds with its receptor Mas, exerting benefical effects in cerebrovascular disease. Through interacting with nitric oxide and bradykinin, Ang-(1-7) could attenuate the development of hypertension and the pathologic progress of atherosclerosis. Besides, its antithrombotic activity also prevents thrombogenic events, which may contribute to reduce the risk of ischemic stroke. In addition, after ischemia insult, ACE2-Ang-(1-7)-Mas has been shown to reduce the cerebral infarct size and improve neurological deficits through its antioxidative and anti-inflammatory effects. Taken together, activation of the ACE2-Ang-(1-7)-Mas axis may become a novel therapeutic target in prevention and treatment of ischemia stroke, which deserves further investigations.
doi:10.2174/1570159X11311020007
PMCID: PMC3637674  PMID: 23997755
Renin-angiotensin system; Angiotensin-(1-7); Stroke; Neuroprotection; Oxidative stress.
16.  Inhibition of renin angiotensin aldosterone system causes abrogation of obliterative airways disease through inhibition of tumor necrosis factor-α–dependant interleukin-17 
BACKGROUND
Alloimmune-induced immune responses to self-antigens are involved in the development of chronic lung allograft rejection. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been shown to modulate autoimmune diseases. This study investigated the effect of modulation of the renin angiotensin aldosterone system (RAAS) a murine model of obliterative airways disease (OAD).
METHODS
Major histocompatibility complex (MHC) class I antibodies were administered intrabronchially to C57Bl/6 mice on Days 1, 2, 3, and 6, and weekly thereafter. ACEI/ARB (10 mg/kg/day) were administered in water 5 days before antibody administration. Antibodies were analyzed by enzyme-linked immunosorbent assay, cytokines by Luminex, Th-frequency by enzyme-linked immunosorbent spot, and transcription factors by Western blotting and real-time polymerase chain reaction.
RESULTS
Significant decreases (50%–70%) in airway lesions and fibrous deposition were noted in lungs at Day 30 in the animals administered ACEI and ARB vs controls. Antibody concentrations to self-antigens also decreased from 14 ± 21 to 62 ± 18 μg/ml for collagen V and from 263 ± 43 to 84 ± 28 μg/ml for K-α1 tubulin. Th-precursor frequency and cytokine analysis showed increased interleukin (IL)-10 (3-fold increase) and decreased levels of IL-6 (3.4-fold) and IL-17 (4-fold decrease; p < 0.05) in ACEI and ARB groups. There was also messenger RNA level downregulation of tumor necrosis factor-α (8.6-fold) and p38/mitogen-activated protein (MAP)kinase (3.1-fold) in the treatment groups.
CONCLUSIONS
Our results demonstrate that modulation of RAAS leads to downregulation of IL-17 through tumor necrosis factor-α– dependant IL-6 through p38/MAPKinase pathway and thus abrogation of anti-MHC–induced OAD.
doi:10.1016/j.healun.2011.12.012
PMCID: PMC3462449  PMID: 22289485
renin angiotensis aldosterone system; ACE inhibitors; obliterative airway disease; TNF-alpha; TH-17 pathway
17.  Plasma 25-hydroxyvitamin D and regulation of the Renin Angiotensin System in Humans 
Hypertension  2010;55(5):1283-1288.
Vitamin D regulates the renin angiotensin system in experimental animals, but corresponding human data are limited. We examined the relation between plasma 25-hydroxyvitamin D and elements of the renin angiotensin system in 184 normotensive individuals in high sodium balance; these included circulating levels of plasma renin activity and angiotensin II, and the renal plasma flow response to infused angiotensin II, which is an indirect measure of the intrinsic renin angiotensin system activity in the kidney. Compared to individuals with sufficient 25-hydroxyvitamin D levels (≥ 30 ng/mL), those with insufficiency (15 - 29.9 ng/mL) and deficiency (<15 ng/mL) had higher circulating angiotensin II levels (p-trend = 0.03). Moreover, those with vitamin D deficiency had significantly blunted renal plasma flow responses to infused angiotensin II (mean decrease of 115 mL/min/1.732 in renal plasma flow vs. 145 ml/min/1.73m2 among those with sufficient vitamin D levels; p-trend = 0.009). Although plasma renin activity was higher among individuals with insufficient levels of vitamin D, the result was not statistically significant. These data suggest that low plasma 25-hydroxyvitamin D levels may result in upregulation of the renin angiotensin system in otherwise healthy humans.
doi:10.1161/HYPERTENSIONAHA.109.148619
PMCID: PMC3023301  PMID: 20351344
vitamin D; renin angiotensin system; hypertension; epidemiology; human
18.  Differential clinical profile of candesartan compared to other angiotensin receptor blockers 
The advantages of blood pressure (BP) control on the risks of heart failure and stroke are well established. The renin-angiotensin system plays an important role in volume homeostasis and BP regulation and is a target for several groups of antihypertensive drugs. Angiotensin II receptor blockers represent a major class of antihypertensive compounds. Candesartan cilexetil is an angiotensin II type 1 (AT[1]) receptor antagonist (angiotensin receptor blocker [ARB]) that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system. Oral candesartan 8–32 mg once daily is recommended for the treatment of adult patients with hypertension. Clinical trials have demonstrated that candesartan cilexetil is an effective agent in reducing the risk of cardiovascular mortality, stroke, heart failure, arterial stiffness, renal failure, retinopathy, and migraine in different populations of adult patients including patients with coexisting type 2 diabetes, metabolic syndrome, or kidney impairment. Clinical evidence confirmed that candesartan cilexetil provides better antihypertensive efficacy than losartan and is at least as effective as telmisartan and valsartan. Candesartan cilexetil, one of the current market leaders in BP treatment, is a highly selective compound with high potency, a long duration of action, and a tolerability profile similar to placebo. The most important and recent data from clinical trials regarding candesartan cilexetil will be reviewed in this article.
doi:10.2147/VHRM.S22591
PMCID: PMC3253768  PMID: 22241949
angiotensin receptor blockers; candesartan; candesartan cilexetil; clinical trials; efficacy studies; safety; blood pressure
19.  Suppression of Aldosterone Synthesis and Secretion by Ca2+ Channel Antagonists 
Aldosterone, a specific mineralocorticoid receptor (MR) agonist and a key player in the development of hypertension, is synthesized as a final product of renin-angiotensin-aldosterone system. Hypertension can be generally treated by negating the effects of angiotensin II through the use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin II type 1 receptor antagonists (ARBs). However, the efficacy of angiotensin II blockade by such drugs is sometimes diminished by the so-called “aldosterone breakthrough” effect, by which ACE-Is or ARBs (renin-angiotensin system (RAS) inhibitors) gradually lose their effectiveness against hypertension due to the overproduction of aldosterone, known as primary aldosteronism. Although MR antagonists are used to antagonize the effects of aldosterone, these drugs may, however, give rise to life-threatening adverse actions, such as hyperkalemia, particularly when used in conjunction with RAS inhibitors. Recently, several groups have reported that some dihydropyridine Ca2+ channel blockers (CCBs) have inhibitory actions on aldosterone production in in vitro and in the clinical setting. Therefore, the use of such dihydropyridine CCBs to treat aldosterone-related hypertension may prove beneficial to circumvent such therapeutic problems. In this paper, we discuss the mechanism of action of CCBs on aldosterone production and clinical perspectives for CCB use to inhibit MR activity in hypertensive patients.
doi:10.1155/2012/519467
PMCID: PMC3477571  PMID: 23097668
20.  Update on the Angiotensin Converting Enzyme 2-Angiotensin (1–7)-Mas Receptor Axis: Fetal Programing, Sex Differences, and Intracellular Pathways 
The renin-angiotensin-system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. Indeed, dysregulation of the RAS may lead to the development of cardiovascular pathologies including kidney injury. Moreover, the blockade of this system by the inhibition of angiotensin converting enzyme (ACE) or antagonism of the angiotensin type 1 receptor (AT1R) constitutes an effective therapeutic regimen. It is now apparent with the identification of multiple components of the RAS that the system is comprised of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS can be defined as the ACE-Ang II-AT1R axis that promotes vasoconstriction, sodium retention, and other mechanisms to maintain blood pressure, as well as increased oxidative stress, fibrosis, cellular growth, and inflammation in pathological conditions. In contrast, the non-classical RAS composed of the ACE2-Ang-(1–7)-Mas receptor axis generally opposes the actions of a stimulated Ang II-AT1R axis through an increase in nitric oxide and prostaglandins and mediates vasodilation, natriuresis, diuresis, and oxidative stress. Thus, a reduced tone of the Ang-(1–7) system may contribute to these pathologies as well. Moreover, the non-classical RAS components may contribute to the effects of therapeutic blockade of the classical system to reduce blood pressure and attenuate various indices of renal injury. The review considers recent studies on the ACE2-Ang-(1–7)-Mas receptor axis regarding the precursor for Ang-(1–7), the intracellular expression and sex differences of this system, as well as an emerging role of the Ang1-(1–7) pathway in fetal programing events and cardiovascular dysfunction.
doi:10.3389/fendo.2013.00201
PMCID: PMC3886117  PMID: 24409169
Ang-(1–7); Ala1-Ang-(1–7); ACE2; ACE; Mas receptor; Mas-related receptor D; fetal programing
21.  Renin inhibition with aliskiren in hypertension: focus on aliskiren/hydrochlorothiazide combination therapy 
Vascular Health and Risk Management  2008;4(6):1205-1220.
Hypertension is a major risk factor for the development of cardiovascular and renal disease. The incidence of hypertension is increasing globally and the rate of blood pressure control remains inadequate. Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in volume regulation and maintenance of blood pressure. Pathological activation of RAAS results in chronic hypertension and consequent end organ damage. Most patients with hypertension require combination therapy using agents with complimentary mechanisms of action. Hydrochlorothiazide (HCTZ) together with an agent blocking the RAAS such as an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) are widely used effective anti-hypertensive therapy. Aliskiren is an orally effective direct renin inhibitor that blocks the generation of angiotensin I from angiotensinogen, the rate limiting step of RAAS activation. Studies have shown equivalent antihypertensive efficacy of aliskiren when compared to existing medications such as HCTZ, ACE inhibitors and ARBs. Aliskiren has also been tested in combination therapies. The current review aims to look at the efficacy of aliskiren therapy in hypertension and the evidence for using aliskiren in combination with HCTZ.
PMCID: PMC2663460  PMID: 19337534
hypertension; renin-angiotensin-aldosterone system; aliskiren; aliskiren-hydrochlorothiazide; combination therapy; renin inhibitors
22.  The angiotensin II type 2 receptor and the kidney 
Recent knowledge demonstrated that the renin-angiotensin system (RAS) functions as a local renal paracrine system. All components of the RAS are present within the kidney and include angiotensinogen, renin, angiotensin I, angiotensin-converting enzymes, angiotensin II, the angiotensin II type 1 (AT1) receptor and the angiotensin II type 2 (AT2) receptor. Angiotensin II is the major effector hormone of the RAS and contributes to a variety of renal and cardiovascular physiologic and pathologic mechanisms through stimulation of AT1 and AT2 receptors. Angiotensin receptor blockers were developed based on the advanced knowledge of the AT1 receptor contribution to development of a variety of kidney, vascular and cardiac diseases including but not limited to hypertension, diabetic nephropathy, heart failure, myocardial infarction and atherosclerosis. In contrast, knowledge concerning the role of the AT2 receptor in health and disease is still emerging. The AT2 receptor is believed to counterbalance the effects of the AT1 receptor through influencing cellular differentiation, vasodilation, inhibition of cellular proliferation and hypertrophy, nitric oxide production and natriuresis. Thus, the pursuit of a specific AT2 receptor agonist is a potentially fruitful area for combating renal and cardiovascular diseases. This review focuses on the role of the AT2 receptor in the kidney.
doi:10.1177/1470320309347786
PMCID: PMC3974170  PMID: 19861347
AT2 receptors; cGMP; kidney; nitric oxide
23.  HNF4alpha Dysfunction as a Molecular Rational for Cyclosporine Induced Hypertension 
PLoS ONE  2011;6(1):e16319.
Induction of tolerance against grafted organs is achieved by the immunosuppressive agent cyclosporine, a prominent member of the calcineurin inhibitors. Unfortunately, its lifetime use is associated with hypertension and nephrotoxicity. Several mechanism for cyclosporine induced hypertension have been proposed, i.e. activation of the sympathetic nervous system, endothelin-mediated systemic vasoconstriction, impaired vasodilatation secondary to reduction in prostaglandin and nitric oxide, altered cytosolic calcium translocation, and activation of the renin-angiotensin system (RAS). In this regard the molecular basis for undue RAS activation and an increased signaling of the vasoactive oligopeptide angiotensin II (AngII) remain elusive. Notably, angiotensinogen (AGT) is the precursor of AngII and transcriptional regulation of AGT is controlled by the hepatic nuclear factor HNF4alpha. To better understand the molecular events associated with cyclosporine induced hypertension, we investigated the effect of cyclosporine on HNF4alpha expression and activity and searched for novel HNF4alpha target genes among members of the RAS cascade. Using bioinformatic algorithm and EMSA bandshift assays we identified angiotensin II receptor type 1 (AGTR1), angiotensin I converting enzyme (ACE), and angiotensin I converting enzyme 2 (ACE2) as genes targeted by HNF4alpha. Notably, cyclosporine represses HNF4alpha gene and protein expression and its DNA-binding activity at consensus sequences to AGT, AGTR1, ACE, and ACE2. Consequently, the gene expression of AGT, AGTR1, and ACE2 was significantly reduced as evidenced by quantitative real-time RT-PCR. While RAS is composed of a sophisticated interplay between multiple factors we propose a decrease of ACE2 to enforce AngII signaling via AGTR1 to ultimately result in vasoconstriction and hypertension. Taken collectively we demonstrate cyclosporine to repress HNF4alpha activity through calcineurin inhibitor mediated inhibition of nuclear factor of activation of T-cells (NFAT) which in turn represses HNF4alpha that leads to a disturbed balance of RAS.
doi:10.1371/journal.pone.0016319
PMCID: PMC3029342  PMID: 21298017
24.  Targeting the ACE2-Ang-(1–7) Pathway in Cardiac Fibroblasts to Treat Cardiac Remodeling and Heart Failure 
Fibroblasts play a pivotal role in cardiac remodeling and the development of heart failure through the deposition of extra-cellular matrix (ECM) proteins and also by affecting cardiomyocyte growth and function. The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system in health and disease and many of its effects involve cardiac fibroblasts. Levels of angiotensin II (Ang II), the main effector molecule of the RAS, are elevated in the failing heart and there is a substantial body of evidence indicating that this peptide contributes to changes in cardiac structure and function which ultimately lead to progressive worsening in heart failure. A pathway involving angiotensin converting enzyme 2 (ACE2) has the capacity to break down Ang II while generating angiotensin-(1–7) (Ang-(1–7), a heptapeptide, which in contrast to Ang II, has cardioprotective and anti-remodeling effects. Many Ang-(1–7) actions involve cardiac fibroblasts and there is information indicating that it reduces collagen production and also may protect against cardiac hypertrophy. This report describes the effects of ACE2 and Ang-(1–7) that appear to be relevant in cardiac remodeling and heart failure and explores potential therapeutic strategies designed to increase ACE2 activity and Ang-(1–7) levels to treat these conditions.
doi:10.1016/j.yjmcc.2010.12.003
PMCID: PMC3085048  PMID: 21147120
25.  Liver X receptors α and β regulate renin expression in vivo 
Journal of Clinical Investigation  2005;115(7):1913-1922.
The renin-angiotensin-aldosterone system controls blood pressure and salt-volume homeostasis. Renin, which is the first enzymatic step of the cascade, is critically regulated at the transcriptional level. In the present study, we investigated the role of liver X receptor α (LXRα) and LXRβ in the regulation of renin. In vitro, both LXRs could bind to a noncanonical responsive element in the renin promoter and regulated renin transcription. While LXRα functioned as a cAMP-activated factor, LXRβ was inversely affected by cAMP. In vivo, LXRs colocalized in juxtaglomerular cells, in which LXRα was specifically enriched, and interacted with the renin promoter. In mouse models, renin-angiotensin activation was associated with increased binding of LXRα to the responsive element. Moreover, acute administration of LXR agonists was followed by upregulation of renin transcription. In LXRα–/– mice, the elevation of renin triggered by adrenergic stimulation was abolished. Untreated LXRβ–/– mice exhibited reduced kidney renin mRNA levels compared with controls. LXRα–/–LXRβ–/– mice showed a combined phenotype of lower basal renin and blunted adrenergic response. In conclusion, we show herein that LXRα and LXRβ regulate renin expression in vivo by directly interacting with the renin promoter and that the cAMP/LXRα signaling pathway is required for the adrenergic control of the renin-angiotensin system.
doi:10.1172/JCI24594
PMCID: PMC1159146  PMID: 16007255

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