Emergence and evolution of the renin–angiotensin–aldosterone system

The renin-angiotensin-aldosterone system (RAAS) is not the sole, but perhaps the most important volume regulator in vertebrates. To gain insights into the function and evolution of its components, we conducted a phylogenetic analysis of its main related genes. We found that important parts of the system began to appear with primitive chordates and tunicates and that all major components were present at the divergence of bony fish, with the exception of the Mas receptor. The Mas receptor first appears after the bony-fish/tetrapod divergence. This phase of evolutionary innovation happened about 400 million years ago. We found solid evidence that angiotensinogen made its appearance in cartilage fish. The presence of several RAAS genes in organisms that lack all the components shows that these genes have had other ancestral functions outside of their current role. Our analysis underscores the utility of sequence comparisons in the study of evolution. Such analyses may provide new hypotheses as to how and why in today's population an increased activity of the RAAS frequently leads to faulty salt and volume regulation, hypertension, and cardiovascular diseases, opening up new and clinically important research areas for evolutionary medicine.     

The role of the renin–angiotensin system in the pathogenesis of preeclampsia – New insights into the renin–angiotensin system in preeclampsia

The renin–angiotensin system (RAS) plays an important role in the pathogenesis of hypertension. However, the role of RAS in preeclampsia is largely unknown, because the plasma concentration of renin and angiotensin (AII) is lower in preeclampsia than in normal pregnancy, whereas its cardinal sign is hypertension. A pressor response to AII infusions can predict the onset of preeclampsia, resulting in involvement of RAS in the pathogenesis of preeclampsia. It has been reported that patients with preeclampsia exhibit angiotensin type I receptor agonistic autoantibody (AT1-AA), suggesting the involvement of RAS in the pathogenesis of this condition. The physiological action of AT1-AA can explain the various clinical symptoms of preeclampsia. However, the significance of circulatory RAS, including AT1-AA, in the pathogenesis of preeclampsia remains obscure. Since many reports state that circulating RAS is thought to be suppressed in preeclampsia it is difficult to explain the onset of hypertension in preeclampsia by circulating RAS. Therefore, I propose new insights into the role of RAS in preeclampsia to resolve the contradiction as above-mentioned. The recent discovery of tissue RAS, on which prorenin and its receptor act, suggests a promising new direction in understanding the role of RAS in the pathogenesis of preeclampsia.     

Angiotensin receptor-associated proteins: local modulators of the renin–angiotensin system

The activity of the renin–angiotensin system crucially depends on the rate of renal renin secretion. Changes in renin secretion result in fluctuations of angiotensin II concentrations in the circulation and subsequently in the activation of angiotensin receptors in all accessible target organs. Consequently, various mechanisms have evolved to regulate the local sensitivity to angiotensin II. In this review, an overview of angiotensin II receptor-associated proteins is addressed. These proteins regulate the local sensitivity of receptor-expressing cells by modulating the receptor surface expression and the receptor sensitivity. A hypothesis will be discussed that integrates the existence of various angiotensin receptor-associated proteins into an overall functional model.     

Influence and implications of the renin–angiotensin–aldosterone system in obstructive sleep apnea: An updated systematic review and meta-analysis

Obstructive sleep apnea is a chronic, sleep-related breathing disorder, which is an independent risk factor for cardiovascular disease. The renin–angiotensin–aldosterone system regulates salt and water homeostasis, blood pressure, and cardiovascular remodelling. Elevated aldosterone levels are associated with excess morbidity and mortality. We aimed to analyse the influence and implications of renin–angiotensin–aldosterone system derangement in individuals with and without obstructive sleep apnea. We pooled data from 20 relevant studies involving 2828 participants (1554 with obstructive sleep apnea, 1274 without obstructive sleep apnea). The study outcomes were the levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate. Patients with obstructive sleep apnea had higher levels of plasma renin activity (pooled wmd+ 0.25 [95% confidence interval 0.04–0.46], p = 0.0219), plasma aldosterone (pooled wmd+ 30.79 [95% confidence interval 1.05–60.53], p = 0.0424), angiotensin II (pooled wmd+ 5.19 [95% confidence interval 3.11–7.27], p < 0.001), systolic (pooled wmd+ 5.87 [95% confidence interval 1.42–10.32], p = 0.0098) and diastolic (pooled wmd+ 3.40 [95% confidence interval 0.86–5.94], p = 0.0086) blood pressure, and heart rate (pooled wmd+ 3.83 [95% confidence interval 1.57–6.01], p = 0.0009) compared with those without obstructive sleep apnea. The elevation remained significant (except for renin levels) when studies involving patients with resistant hypertension were removed. Sub-group analysis demonstrated that levels of angiotensin II were significantly higher only among the Asian population with obstructive sleep apnea compared with those without obstructive sleep apnea. Body mass index accounted for less than 10% of the between-study variance in elevation of the renin–angiotensin–aldosterone system parameters. Patients with obstructive sleep apnea have higher levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate compared with those without obstructive sleep apnea, which remains significant even among patients without resistant hypertension.     

Metabolic rate regulation by the renin–angiotensin system: brain vs. body

Substantial evidence supports a role for the renin–angiotensin system (RAS) in the regulation of metabolic function, but an apparent paradox exists where genetic or pharmacological inhibition of the RAS occasionally has similar physiological effects as chronic angiotensin infusion. Similarly, while RAS targeting in animal models has robust metabolic consequences, effects in humans are more subtle. Here, we review the data supporting a role for the RAS in metabolic rate regulation and propose a model where the local brain RAS works in opposition to the peripheral RAS, thus helping to explain the paradoxically similar effects of RAS supplementation and inhibition. Selectively modulating the peripheral RAS or brain RAS may thus provide a more effective treatment paradigm for obesity and obesity-related disorders.     

Update on tissue renin–angiotensin systems

Angiotensin (Ang) II is not only generated in the circulation by renin and angiotensin-converting enzyme (ACE) but also is produced locally in numerous organs including kidney, vessels, heart, adrenal gland, eye, testis, and brain. Furthermore, widely distributed mast cells have been shown to be a production site. Local Ang II production process is commonly termed the result of a “tissue” renin–angiotensin system (RAS). Because pharmacological experiments do not easily allow targeting of specific tissues, many novel findings about the functional importance of tissue RAS have been collected from transgenic rodent models. These animals either overexpress or lack RAS components in specific tissues and thereby elucidate their local functions. The data to date show that in most tissues local RAS amplify the actions of circulating Ang II with important implications for physiology and pathophysiology of cardiovascular diseases. This review summarizes the recent findings on the importance of tissue RAS in the most relevant cardiovascular organs.     

Blockade of the renin–angiotensin system inhibits growth of colorectal cancer liver metastases in the regenerating liver

Partial hepatectomy (PH), the preferred option for selected patients with colorectal cancer liver metastases (CRCLM), is associated with 40–80 % tumor recurrence rates. Renin–angiotensin system (RAS) blockade inhibits tumor growth and has been suggested to improve liver regeneration. We documented the effect of RAS blockade on tumor growth and liver regeneration in a murine model. CRCLM induction followed by 70 % PH was performed on 78 CBA mice. Liver regeneration (days 2, 6) and CRCLM tumor load were measured by liver (and tumor) weights, percentage of CRCLM burden and tumor nodule count (days 16, 21). mRNA expression of the RAS components was characterised. Statistical analysis was performed using 2-independent sample T test or Mann–Whitney test (SPSS). Captopril did not impair liver regeneration. By day 21, Captopril decreased tumor burden (percentage of CRCLM in the liver) (48.7 ± 4.7 % control, 24.4 ± 6.2 Captopril; p = 0.008), tumor volume (1046.2 ± 200.2 mm³, 388.3 ± 150.4; p = 0.02), tumor nodule count per image field (181.1 ± 28.5, 68 ± 17.6; p = 0.005) and tumor angiogenesis (71.8 ± 6.4 vessels/mm², 43.1 ± 7.6; p = 0.015) compared to controls. Captopril enhanced tumor apoptosis (1 ± 0.2 %, 2.5 ± 0.7; p = 0.028). Liver regeneration and tumor development increased liver ACE levels. Blockade of the RAS effectively retarded CRCLM tumor growth at the late stage of tumor development within the regenerating liver without impeding liver regeneration following PH, via anti-angiogenesis and pro-tumor apoptosis. Captopril may be of therapeutic benefit in patients undergoing PH for CRCLM.     

Combinational effect of genes for the renin–angiotensin system in conferring susceptibility to diabetic nephropathy

To elucidate the role of the renin–angiotensin system (RAS) in diabetic nephropathy, we examined the association between diabetic nephropathy in a large cohort of Japanese type 2 diabetic patients and polymorphisms within the genes that encode angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II receptor type 1 (AGTR1). Single nucleotide polymorphisms (SNPs) within these genes were genotyped using invader assay in 747 nephropathy cases and 557 control subjects. Eight SNPs within the ACE gene were significantly associated with diabetic nephropathy (P<0.05), including five SNPs in almost complete linkage disequilibrium to the insertion/deletion polymorphism in the 16th intron (P=0.01, odds ratio =1.34, 95% CI 1.07–1.69). Three SNPs within the AGT, including M235T and one SNP in the AGTR1, were also significantly associated with nephropathy (M235T P=0.01, odds ratio =0.74, 95% CI 0.59–0.94). In addition, we found that the allelic mRNA expression corresponding to the 235M allele was significantly higher than that for the 235T allele in normal kidney tissues. Furthermore, we found a significant additional effect of these three genes by a step-wise logistic regression analysis (final empirical P value =0.00005). We concluded that RAS gene polymorphisms may contribute to the susceptibility to diabetic nephropathy in type 2 diabetes. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

The role of the brain renin–angiotensin system in hypertension: Implications for new treatment

Hypertension affects 26% of adults and is in constant progress related to increased incidence of obesity and diabetes. One-third of hypertensive patients may be successfully treated with one antihypertensive agent, one-third may require two agents and in the remaining patients will need three agents for effective blood pressure (BP) control. The development of new classes of antihypertensive agents with different mechanisms of action therefore remains an important goal. Brain renin–angiotensin system (RAS) hyperactivity has been implicated in hypertension development and maintenance in several types of experimental and genetic hypertension animal models. Among the main bioactive peptides of the brain RAS, angiotensin (Ang) II and Ang III have similar affinities for type 1 (AT1) and type 2 (AT2) Ang II receptors. Following intracerebroventricular (i.c.v.) injection, Ang II and Ang III similarly increase arginine–vasopressin (AVP) release and BP. Blocking the brain RAS may be advantageous as it simultaneously (1) decreases sympathetic tone and consequently vascular resistance, (2) decreases AVP release, reducing blood volume and vascular resistance and (3) blocks angiotensin-induced baroreflex inhibition, decreasing both vascular resistance and cardiac output. However, as Ang II is converted to Ang III in vivo, the exact nature of the active peptide is not precisely determined. We summarize here the main findings identifying AngIII as one of the major effector peptides of the brain RAS in the control of AVP release and BP. Brain AngIII exerts a tonic stimulatory effect on BP in hypertensive rats, identifying brain aminopeptidase A (APA), the enzyme generating brain Ang III, as a potentially candidate target for hypertension treatment. This has led to the development of potent orally active APA inhibitors, such as RB150 — the prototype of a new class of centrally acting antihypertensive agents.     

Expression of angiotensinogen and receptors for angiotensin and prorenin in the monkey and human substantia nigra: an intracellular renin–angiotensin system in the nigra

We have previously obtained in rodents a considerable amount of data suggesting a major role for the brain renin–angiotensin system (RAS) in dopaminergic neuron degeneration and potentially in Parkinson’s disease. However, the presence of a local RAS has not been demonstrated in the monkey or the human substantia nigra compacta (SNc). The present study demonstrates the presence of major RAS components in dopaminergic neurons, astrocytes and microglia in both the monkey and the human SNc. Angiotensin type 1 and 2 and renin–prorenin receptors were located at the surface of dopaminergic neurons and glial cells, as expected for a tissular RAS. However, angiotensinogen and receptors for angiotensin and renin–prorenin were also observed at the cytoplasm and nuclear level, which suggests the presence of an intracrine or intracellular RAS in monkey and human SNc. Although astrocytes and microglia were labeled for angiotensin and prorenin receptors in the normal SNc, most glial cells appeared less immunoreactive than the dopaminergic neurons. However, our previous studies in rodent models of PD and studies in other animal models of brain diseases suggest that the RAS activity is significantly upregulated in glial cells in pathological conditions. The present results together with our previous findings in rodents suggest a major role for the nigral RAS in the normal functioning of the dopaminergic neurons, and in the progression of the dopaminergic degeneration.     

The brain renin–angiotensin system: a diversity of functions and implications for CNS diseases

The classic renin–angiotensin system (RAS) was initially described as a hormone system designed to mediate cardiovascular and body water regulation, with angiotensin II as its major effector. The discovery of an independent local brain RAS composed of the necessary functional components (angiotensinogen, peptidases, angiotensins, and specific receptor proteins) significantly expanded the possible physiological and pharmacological functions of this system. This review first describes the enzymatic pathways resulting in active angiotensin ligands and their interaction with AT₁, AT₂, and AT₄ receptor subtypes. Next, we discuss the classic physiologies and behaviors controlled by the RAS including cardiovascular, thirst, and sodium appetite. A final section summarizes non-classic functions and clinical conditions mediated by the brain RAS with focus on memory and Alzheimer’s disease. There is no doubt that the brain RAS is an important component in the development of dementia. It also appears to play a role in normal memory consolidation and retrieval. The presently available anti-dementia drugs are proving to be reasonably ineffective, thus alternative treatment approaches must be developed. At the same time, presently available drugs must be tested for their efficacy to treat newly identified syndromes and diseases connected with the RAS. The list of non-classic physiologies and behaviors is ever increasing in both number and scope, attesting to the multidimensional influences of the RAS. Such diversity in function presents a dilemma for both researchers and clinicians. Namely, the blunting of RAS subsystems in the hopes of combating one constellation of underlying causes and disease symptoms may be counter-balanced by unanticipated and unwanted consequences to another RAS subsystem. For example, the use of angiotensin-converting enzyme inhibitors and AT₁ and/or AT₂ receptor blockers have shown great promise in the treatment of cardiovascular related pathologies; however, their use could negate the cerebroprotective benefits offered by this system.     

Contribution of renin–angiotensin system to exercise-induced attenuation of aortic remodeling and improvement of endothelial function in spontaneously hypertensive rats

IntroductionIt is well known that exercise alleviates aortic remodeling and preserves endothelial function in spontaneously hypertensive rats (SHRs). However, the underlying molecular mechanism remains unclear. This study aimed to investigate the role of renin–angiotensin system (RAS) components in exercise-induced attenuation of aortic remodeling and improvement of endothelial function in an animal model of human essential hypertension.MethodsThe 10-week-old male SHR and age-matched normotensive Wistar–Kyoto rats were given moderate-intensity exercise for 12 weeks (four groups, n= 80–86 in each group).ResultsIn this work, exercise training reduced blood pressure and effectively attenuated aortic remodeling, marked by a reduction in aortic weight/length, wall thickness, and aortic levels of elastin and hydroxyproline, and improved endothelium-mediated vascular relaxations of aortas in response to acetylcholine. Exercise training in SHR reduced angiotensin II (AngII) levels and enhanced Ang-(1–7) levels in aortas. Exercise training in SHR suppressed aortic angiotensin-converting enzyme (ACE) and AngII type 1 receptor (AT1R) messenger RNA (mRNA) levels and protein expression and up-regulated ACE2, AngII type 2 receptor, and Mas mRNA levels and protein expression. In addition, exercise training in SHR increased levels of microRNA-27a (targeting ACE) and microRNA-155 (targeting AT1R) and decreased levels of microRNA-143 (targeting ACE2) in the aortas.ConclusionChronic aerobic exercise training improved RAS balance in the aortas, which may in part explain the protective effect of exercise on aortic function and structure.SummaryChronic aerobic exercise training improved RAS balance in the aortas, which may explain the protective effect of exercise on aortic function and structure, at least in part.     

Exome sequencing–based molecular autopsy of formalin-fixed paraffin-embedded tissue after sudden death

PurposeSudden death in the young is a devastating complication of inherited heart disorders. Finding the precise cause of death is important, but it is often unresolved after postmortem investigation. The addition of postmortem genetic testing, i.e., the molecular autopsy, can identify additional causes of death. We evaluated DNA extracted from formalin-fixed paraffin-embedded postmortem tissue for exome sequencing–based molecular autopsy after sudden death in the young.MethodsWe collected clinical and postmortem information from patients with sudden death. Exome sequencing was performed on DNA extracted from fixed postmortem tissue. Variants relevant to the cause of death were sought.ResultsFive patients with genetically unresolved sudden death were recruited. DNA extracted from fixed postmortem tissue was degraded. Exome sequencing achieved 20-fold coverage of at least 82% of coding regions. A threefold excess of singleton variants was found in the exome sequencing data of one patient. We found a de novo SCN1A frameshift variant in a patient with sudden unexpected death in epilepsy and a LMNA nonsense variant in a patient with dilated cardiomyopathy.ConclusionDNA extracted from fixed postmortem tissue is applicable to exome sequencing–based molecular autopsy. Fixed postmortem tissues are an untapped resource for exome-based studies of rare causes of sudden death.Genet Med advance online publication 23 March 2017     

Are lethal audiogenic seizures a missing link to the sudden infant death syndrome?

The pathogenesis of human seizure disorders has largely been derived from rodent models. A number of rodent and chick strains exhibit a genetic predisposition for lethal audiogenic seizures (AGSs) in the first year of life. Consideration is warranted that this disorder may be linked to the sudden infant death syndrome (SIDS). Factors that carry a strong association with SIDS such as hyperthermia and the prone sleeping position would conceivably play a significant role in a human AGS syndrome. Importantly, there is data to support the likelihood that motor seizure activity may be absent in infants with an AGS syndrome. Rodent AGSs may hold important clues to unraveling the mystery of SIDS.