Increased Renin-angiotensin System Activity Research Articles

Prenatal LPS leads to increases in RAS expression within the PVN and overactivation of sympathetic outflow in offspring rats.

The renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) are two major blood pressure-regulating systems. The link between the renal and cerebral RAS axes was provided by reflex activation of renal afferents and efferent sympathetic nerves. There is a self-sustaining enhancement of the brain and the intrarenal RAS. In this study, prenatal exposure to lipopolysaccharide (LPS) led to increased RAS activity in the paraventricular nucleus (PVN) and overactivation of sympathetic outflow, accompanied by increased production of reactive oxygen species (ROS) and disturbances between inhibitory and excitatory neurons in PVN. The AT1 receptor blocker losartan and α2 adrenergic receptor agonist clonidine in the PVN significantly decreased renal sympathetic nerve activity (RSNA) and synchronously reduced systolic blood pressure. Prenatal LPS stimulation caused H3 acetylation at H3K9 and H3K14 in the PVN, which suggested that epigenetic changes are involved in transmitting the prenatal adverse stimulative information to the next generation. Additionally, melatonin treatment during pregnancy reduced RAS activity and ROS levels in the PVN; balanced the activity of inhibitory and excitatory neurons in the PVN; increased urine sodium secretion; reduced RSNA and blood pressure. In conclusion, prenatal LPS leads to increased RAS expression within the PVN and overactivation of the sympathetic outflow, thereby contributing to hypertension in offspring rats. Melatonin is expected to be a promising agent for preventing prenatal LPS exposure-induced hypertension.

Inverse Salt Sensitivity of Blood Pressure Is Associated with an Increased Renin-Angiotensin System Activity.

High and low sodium diets are associated with increased blood pressure and cardiovascular morbidity and mortality. The paradoxical response of elevated BP in low salt diets, aka inverse salt sensitivity (ISS), is an understudied vulnerable 11% of the adult population with yet undiscovered etiology. A linear relationship between the number of single nucleotide polymorphisms (SNPs) in the dopamine D2 receptor (DRD2, rs6276 and 6277), and the sodium myo-inositol cotransporter 2 (SLC5A11, rs11074656), as well as decreased expression of these two genes in urine-derived renal proximal tubule cells (uRPTCs) isolated from clinical study participants suggest involvement of these cells in ISS. Insight into this newly discovered paradoxical response to sodium is found by incubating cells in low sodium (LS) conditions that unveil cell physiologic differences that are then reversed by mir-485-5p miRNA blocker transfection and bypassing the genetic defect by DRD2 re-expression. The renin-angiotensin system (RAS) is an important counter-regulatory mechanism to prevent hyponatremia under LS conditions. Oversensitive RAS under LS conditions could partially explain the increased mortality in ISS. Angiotensin-II (AngII, 10 nmol/L) increased sodium transport in uRPTCs to a greater extent in individuals with ISS than SR. Downstream signaling of AngII is verified by identifying lowered expression of nuclear factor erythroid 2-related factor 2 (NRF2), CCCTC-binding factor (CTCF), and manganese-dependent mitochondrial superoxide dismutase (SOD2) only in ISS-derived uRPTCs and not SR-derived uRPTCs when incubated in LS conditions. We conclude that DRD2 and SLC5A11 variants in ISS may cause an increased low sodium sensitivity to AngII and renal sodium reabsorption which can contribute to inverse salt-sensitive hypertension.

ANGIOTENSIN PROFILES IN PATIENTS WITH HYPERTENSION AND TYPE 2 DIABETES WITH COMBINATION THERAPY OF EMPAGLIFLOZIN AND LINAGLIPTIN VERSUS METFORMIN AND INSULIN GLARGINE

Objective: The renin-angiotensin system (RAS) plays a key role in the physiological regulation of blood pressure. Patients with type-2-diabetes-mellitus (T2DM) and hypertension are known to have increased RAS activity. However, the precise role of RAS activation after SGLT2-inhibitor therapy is unknown. The classic RAS comprises the ACE-AngII-AT1R-axis (classic-axis) that promotes vasoconstriction. The Angiotensin-converting-enzyme-2-angiotensin-(1–7)-Mas axis (Mas-axis) with its components Angiotensin-(1–7) (Ang-1–7) and Angiotensin-(1–5) (Ang-1–5) is an endogenous negative regulatory pathway of the classic-axis, which can reduce its harmful effects. Design and method: Angiotensin profiles were determined in 55 patients with hypertension and T2DM from our double blind, randomized, placebo controlled clinical trial “Effects of Empagliflozin+Linagliptin (E+L) vs Metformin+Insulin Glargine (M+I) on Renal and Vascular Changes in Type 2 Diabetes’’ (ELMI) at baseline and three months after application of either E+L or M+I. An LC-MS/MS based approach was used to simultaneously quantify individual angiotensin metabolites (Attoquant Diagnostics, Vienna, Austria). Results: In the E+L group medication induced a rise in Ang-I, Ang-(1–7) and a trend to a rise in Ang-II between baseline and treatment, which was not present in the M+I group (table). Comparison between the E+L and M+I group revealed that change between baseline and treatment was significantly different for Ang I (p = 0.002) and Ang-(1–7) (p = 0.002) between the groups. No difference in change between baseline and treatment was found for Ang II (p = 0.182) and Ang-(1–5) (p = 0.224) between the E+L and M+I group. Conclusions: In patients with hypertension and T2DM three months of therapy with E+L led to a rise of classic and protective components of the RAS, which was not present in the M+I group. The biological consequence of this complex RAS activation remains to be elucidated.

Effects of Epoxyeicosatrienoic Acid-Enhancing Therapy on the Course of Congestive Heart Failure in Angiotensin II-Dependent Rat Hypertension: From mRNA Analysis towards Functional In Vivo Evaluation.

This study evaluates the effects of chronic treatment with EET-A, an orally active epoxyeicosatrienoic acid (EETs) analog, on the course of aorto-caval fistula (ACF)-induced heart failure (HF) in Ren-2 transgenic rats (TGR), a model characterized by hypertension and augmented activity of the renin-angiotensin system (RAS). The results were compared with standard pharmacological blockade of the RAS using angiotensin-converting enzyme inhibitor (ACEi). The rationale for employing EET-A as a new treatment approach is based on our findings that apart from increased RAS activity, untreated ACF TGR also shows kidney and left ventricle (LV) tissue deficiency of EETs. Untreated ACF TGR began to die 17 days after creating ACF and were all dead by day 84. The treatment with EET-A alone or ACEi alone improved the survival rate: in 156 days after ACF creation, it was 45.5% and 59.4%, respectively. The combined treatment with EET-A and ACEi appeared to improve the final survival to 71%; however, the difference from either single treatment regimen did not reach significance. Nevertheless, our findings support the notion that targeting the cytochrome P-450-dependent epoxygenase pathway of arachidonic acid metabolism should be considered for the treatment of HF.

Sarcopenia and COVID-19: A Manifold Insight on Hypertension and the Renin Angiotensin System.

Sarcopenia and COVID-19: A Manifold Insight on Hypertension and the Renin Angiotensin System.

Central AT1 receptor signaling by circulating angiotensin II is permissive to acute intermittent hypoxia-induced sympathetic neuroplasticity.

Acute intermittent hypoxia (AIH) triggers sympathetic long-term facilitation (sLTF), a progressive increase in sympathetic nerve activity (SNA) linked to central AT1 receptor (AT1R) activation by circulating angiotensin II (ANG II). Here, we investigated AIH activation of the peripheral renin-angiotensin system (RAS) and the extent to which the magnitude of RAS activation predicts the magnitude of AIH-induced sLTF. In anesthetized male Sprague-Dawley rats, plasma renin activity (PRA) increased in a linear fashion in response to 5 (P = 0.0342) and 10 (P < 0.0001) cycles of AIH, with PRA remaining at the 10th cycle level 1 h later, a period over which SNA progressively increased. On average, SNA ramping began at the AIH cycle 4.6 ± 0.9 (n = 12) and was similar in magnitude 1 h later whether AIH consisted of 5 or 10 cycles (n = 6/group). Necessity of central AT1R in post-AIH sLTF was affirmed by intracerebroventricular (icv) losartan (40 nmol, 2 µL; n = 5), which strongly attenuated both splanchnic (P = 0.0469) and renal (P = 0.0018) sLTF compared with vehicle [artificial cerebrospinal fluid (aCSF), 2 µL; n = 5]. Bilateral nephrectomy largely prevented sLTF, affirming the necessity of peripheral RAS activation. Sufficiency of central ANG II signaling was assessed in nephrectomized rats. Whereas ICV ANG II (0.5 ng/0.5 µL, 30 min) in nephrectomized rats exposed to sham AIH (n = 4) failed to cause SNA ramping, it rescued sLTF in nephrectomized rats exposed to five cycles of AIH [splanchnic SNA (SSNA), P = 0.0227; renal SNA (RSNA), P = 0.0390; n = 5]. Findings indicate that AIH causes progressive peripheral RAS activation, which stimulates an apparent threshold level of central AT1R signaling that plays a permissive role in triggering sLTF.NEW & NOTEWORTHY Acute intermittent hypoxia (AIH) triggers sympathetic long-term facilitation (sLTF) that relies on peripheral renin-angiotensin system (RAS) activation. Here, increasing AIH cycles from 5 to 10 proportionally increased RAS activity, but not the magnitude of post-AIH sLTF. Brain angiotensin II (ANG II) receptor blockade and nephrectomy each largely prevented sLTF, whereas central ANG II rescued it following nephrectomy. Peripheral RAS activation by AIH induces time-dependent neuroplasticity at an apparent central ANG II signaling threshold, triggering a stereotyped sLTF response.

Cardioprotective effects of angiotensin converting Enzyme II

To circumvent the major threats of low blood volume and low blood pressure, animals need powerful mechanisms for salt and water conservation, which is renin–angiotensin system (RAS). Activation of RAS is therefore a useful response in many demanding situations. However, an increased activity of the RAS, especially in combination with other cardiovascular risk factors, may lead to a cascade of deleterious effects such as hypertension, atherosclerosis, myocardial remodeling, heart failure, ischemic stroke, and diabetes mellitus. Many of these pathophysiological actions of angiotensin II (Ang II) may still be viewed as being homeostatic in principle but harmful if carried to excess. Numerous experimental studies have indicated that angiotensin-converting enzyme II (ACE II) efficiently hydrolyzes the potent vasoconstrictor Ang II to Ang 1–7. Thus, the axis formed by ACE II/Ang 1–7/Mas appears to represent an endogenous counter-regulatory pathway within the RAS, the actions of which are in opposition to the vasoconstrictor/proliferative arm of the RAS consisting of ACE, Ang II, and Ang II Type 1 receptor (AT1R). Although most of the well-known cardiovascular and renal effects of RAS are attributed to ACE, an important enzyme in the generation of Ang II, much less is known about the functions of ACE II. This review summarizes recently published data on the basic properties of ACE II and Ang 1–7 and a summary of the evidence from experimental and clinical studies of various pathological conditions related to the biological roles of ACE II/Ang 1–7/Mas in the heart.

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Objective: Changes in the renin-angiotensin system (RAS), known for its critical role in the regulation of blood pressure and sodium homeostasis, may contribute to aging and age-related diseases. Here we characterized the RAS and kidney pathology in mice with genomic instability due to a defective nucleotide excision repair gene (Ercc1d/- mice). These mice display premature features of aging, including vascular dysfunction. Design and method: Studies were performed in male and female Ercc1d/- mice and their wild type controls (Ercc1+/+) at the age of 12 or 18 weeks before and after treatment with losartan. The renin-activatable near-infrared fluorescent probe ReninSense 680™ was applied in vivo to allow non-invasive imaging of renin activity. Plasma renin concentrations (PRC) were additionally measured ex vivo by quantifying Ang I generation in the presence of excess angiotensinogen. Kidneys were harvested and examined for markers of aging, and albumin was determined in urine. Results: Kidneys of 12-week old Ercc1d/- mice showed signs of aging, including tubular anisokaryosis, cell-senescence and increased apoptosis. This was even more pronounced at the age of 18 weeks. Yet, urinary albumin was normal at 12 weeks. The ReninSense 680™ probe showed increased intrarenal renin activity in Ercc1d/- mice versus Ercc1+/+ mice, both at 12 and 18 weeks of age, while PRC in these mice tended to be lower compared to Ercc1+/+ mice. Renin was higher in male than female mice, both in the kidney and in plasma, and losartan increased kidney and plasma renin in both Ercc1d/- and Ercc1+/+ mice. Conclusions: Rapidly aging Ercc1d/- mice display an activated intrarenal RAS, as evidenced by the increased fluorescence detected with the ReninSense 680™ probe. This increased RAS activity may contribute to the disturbed kidney pathology in these mice. The increased intrarenal activity detected with the ReninSense 680™ probe in male vs. female mice, as well as after losartan treatment, are in full agreement with the literature, and thus not only validate the specificity of the probe, but also support its use for longitudinal imaging of altered RAS signaling in aging.

Angiotensinase C mRNA and Protein Downregulations Are Involved in Ethanol-Deteriorated Left Ventricular Systolic Dysfunction in Spontaneously Hypertensive Rats.

The influences of angiotensinase C on ethanol-induced left ventricular (LV) systolic function were assessed in spontaneously hypertensive rats (SHRs). SHRs were fed by a liquid diet with or without ethanol for 49 days. The normotensive Wistar Kyoto rats (WKY) were fed by the liquid diet without ethanol and used as control. We evaluated LV systolic function, angiotensinase C mRNA and protein expressions, activation of the renin-angiotensin system (RAS), and the gene expressions of LV collagen (Col) III a1 and matrix metalloproteinases- (MMP-) 9. Compared to the WKY, LV systolic dysfunction (expressed by decreased fractional shortening and ejection fraction) was observed in the SHRs before ethanol treatment and further deteriorated by ethanol treatment. In the ethanol-treated SHRs, the following were observed: downregulations of angiotensinase C mRNA and protein, increased RAS activity with low collagen production as evidenced by angiotensin II and angiotensin type 1 receptor (AT1R) protein upregulation, AT1aR mRNA downregulation, and an MMP-9 mRNA expression upregulation trend with the downregulation of Col III a1 mRNA expression in LV. We conclude that chronic ethanol regimen is sufficient to promote the enhanced RAS activity-induced decrease in the production of cardiac collagen via downregulated angiotensinase C, leading to the further deterioration of LV systolic dysfunction in SHRs.

Serum uric acid level, blood pressure, and vascular angiotensin II responsiveness in healthy men and women.

Uric acid is associated with hypertension and increased renin–angiotensin system activity, although this relationship diminishes after chronic exposure to high levels. Uric acid is more strongly associated with poor outcomes in women compared to men, although whether this is due to a sex‐specific uric acid‐mediated pathophysiology or reflects sex differences in baseline uric acid levels remains unknown. We examined the association between uric acid and vascular measures at baseline and in response to angiotensin‐II challenge in young healthy humans. Fifty‐two subjects (17 men, 35 premenopausal women) were studied in high‐salt balance. Serum uric acid levels were significantly higher in men compared to women (328 ± 14 μmol/L vs. 248 ± 10 μmol/L, P < 0.001), although all values were within normal sex‐specific range. Men demonstrated no association between uric acid and blood pressure, either at baseline or in response to angiotensin‐II. In stark contrast, a significant association was observed between uric acid and blood pressure at baseline (systolic blood pressure, P = 0.005; diastolic blood pressure, P = 0.02) and in response to angiotensin‐II (systolic blood pressure, P = 0.035; diastolic blood pressure, P = 0.056) in women. However, this sex difference lost significance after adjustment for baseline uric acid. When all subjects were stratified according to high (>300 μmol/L) or low (≤300 μmol/L) uric acid levels, only the low uric acid group showed a positive association between uric acid and measures of vascular tone at baseline and in response to angiotensin‐II. Differences in uric acid‐mediated outcomes between men and women likely reflect differences in exposure to increased uric acid levels, rather than a sex‐specific uric acid‐mediated pathophysiology.

Toll-like receptor 4 upregulation by angiotensin II contributes to hypertension and vascular dysfunction through reactive oxygen species production.

Hypertension is considered as a low-grade inflammatory disease, with adaptive immunity being an important mediator of this pathology. TLR4 may have a role in the development of several cardiovascular diseases; however, little is known about its participation in hypertension. We aimed to investigate whether TLR4 activation due to increased activity of the renin-angiotensin system (RAS) contributes to hypertension and its associated endothelial dysfunction. For this, we used aortic segments from Wistar rats treated with a non-specific IgG (1 µg/day) and SHRs treated with losartan (15 mg/kg·day), the non-specific IgG or the neutralizing antibody anti-TLR4 (1 µg/day), as well as cultured vascular smooth muscle cells (VSMC) from Wistar and SHRs. TLR4 mRNA levels were greater in the VSMC and aortas from SHRs compared with Wistar rats; losartan treatment reduced those levels in the SHRs. Treatment of the SHRs with the anti-TLR4 antibody: 1) reduced the increased blood pressure, heart rate and phenylephrine-induced contraction while it improved the impaired acetylcholine-induced relaxation; 2) increased the potentiation of phenylephrine contraction after endothelium removal; and 3) abolished the inhibitory effects of tiron, apocynin and catalase on the phenylephrine-induced response as well as its enhancing effect of acetylcholine-induced relaxation. In SHR VSMCs, angiotensin II increased TLR4 mRNA levels, and losartan reduced that increase. CLI-095, a TLR4 inhibitor, mitigated the increases in NAD(P)H oxidase activity, superoxide anion production, migration and proliferation that were induced by angiotensin II. In conclusion, TLR4 pathway activation due to increased RAS activity is involved in hypertension, and by inducing oxidative stress, this pathway contributes to the endothelial dysfunction associated with this pathology. These results suggest that TLR4 and innate immunity may play a role in hypertension and its associated end-organ damage.

Brain renin-angiotensin system and dopaminergic cell vulnerability.

Although the renin-angiotensin system (RAS) was classically considered as a circulating system that regulates blood pressure, many tissues are now known to have a local RAS. Angiotensin, via type 1 receptors, is a major activator of the NADPH-oxidase complex, which mediates several key events in oxidative stress (OS) and inflammatory processes involved in the pathogenesis of major aging-related diseases. Several studies have demonstrated the presence of RAS components in the basal ganglia, and particularly in the nigrostriatal system. In the nigrostriatal system, RAS hyperactivation, via NADPH-oxidase complex activation, exacerbates OS and the microglial inflammatory response and contributes to progression of dopaminergic degeneration, which is inhibited by angiotensin receptor blockers and angiotensin converting enzyme (ACE) inhibitors. Several factors may induce an increase in RAS activity in the dopaminergic system. A decrease in dopaminergic activity induces compensatory upregulation of local RAS function in both dopaminergic neurons and glia. In addition to its role as an essential neurotransmitter, dopamine may also modulate microglial inflammatory responses and neuronal OS via RAS. Important counterregulatory interactions between angiotensin and dopamine have also been observed in several peripheral tissues. Neurotoxins and proinflammatory factors may also act on astrocytes to induce an increase in RAS activity, either independently of or before the loss of dopamine. Consistent with a major role of RAS in dopaminergic vulnerability, increased RAS activity has been observed in the nigra of animal models of aging, menopause and chronic cerebral hypoperfusion, which also showed higher dopaminergic vulnerability. Manipulation of the brain RAS may constitute an effective neuroprotective strategy against dopaminergic vulnerability and progression of Parkinson’s disease.

IgA nephropathy with early kidney disease is associated with increased arterial stiffness and renin–angiotensin system activity

IgA nephropathy is associated with increased cardiovascular risk, though whether this is due to loss of kidney function or proteinuria is unclear. For this study 10 normotensive IgA nephropathy subjects with early kidney disease (41±5 yrs, glomerular filtration rate (GFR) 87±9 ml/min, proteinuria 720±300 mg/d) and 10 gender- and blood pressure-matched healthy controls (36±1 yrs, estimated GFR 102±5 ml/min, proteinuria 70±6 mg/d) were studied in high-salt balance. Blood pressure and arterial stiffness, expressed as pulse wave velocity and aortic augmentation index, were measured at baseline and in response to 60 min of angiotensin II (AngII) infusion. At baseline, IgA nephropathy subjects demonstrated similar pulse wave velocity (8.6±0.7 vs. 8.0±0.4 m/s, p=0.5) but increased aortic augmentation index (12.6±3.1 vs. 1.8±4%, p=0.04) and a trend towards increased circulating renin-angiotensin system (RAS) components (plasma renin activity, 0.55±0.18 vs. 0.21±0.05 ng/l/s, p=0.08; angiotensin II, 25±5 vs. 16±1 ng/l, p=0.08) compared with controls. However, despite similar baseline blood pressure values (p=0.8), IgA nephropathy was associated with reduced arterial sensitivity to AngII challenge (Δmean arterial pressure: 19±4 vs. 29±1 mm Hg, p=0.05; Δpulse wave velocity: -0.06±0.6 vs. 1.5±0.3 m/s, p=0.07) compared with controls, even after multivariate analysis. Even in the setting of early kidney disease, IgA nephropathy is associated with increased arterial stiffness and decreased angiotensin II responsiveness, a marker of increased RAS activity.

Loss of cilia increases angiotensin II mediated apical angiotensin‐1‐receptor localization in collecting duct cells

Hypertension (HTN) is frequently present early on in Polycystic Kidney Disease (PKD) before a significant cystic burden has occurred. However, the mechanism for PKD‐induced HTN has not been fully elucidated. The renin‐angiotensin‐system (RAS) is one factor contributing to HTN in PKD, although there are no consistent changes in plasma renin/aldosterone levels in animals or humans with PKD. We hypothesized that intra‐renal‐RAS rather than the systemic RAS may be important in PKD. As an initial approach, we used immortalized collecting duct (CD) cell line derived from Orpk mice with a hypomorphic Ift88 gene resulting in stunted/absent cilia: cilia (−), and Ift88 rescued cells: cilia (+) with normal cilia. There was increased abundance of the angiotensin‐1‐receptor (AT1R) and in (pro) renin in cilia (−) compared to cilia (+) cells. Using biotinylation of apical membranes, 30 min treatment with Ang II (1nM) increased apical AT1R expression in cilia (−) cells but not in cilia (+) cells. Using a GFP‐AT1R construct transfected into these CD cells, we found that with Ang II administration cilia (−) but not cilia (+) cells had predominant luminal membrane localization of GFP‐AT1R. Finally, with addition of Ang II, phospho ERK was increased in cilia (−) compared to cilia (+). Thus, loss of cilia leads to increased abundance of AT1R and the targeting of AT1R to the apical membrane which may lead to increased RAS activity in the CD in PKD.

A Clinical Link Between Peroxisome Proliferator-Activated Receptor γ and the Renin–Angiotensin System

A mechanistic link between peroxisome proliferator-activated receptor γ (PPARγ) and the renin–angiotensin system (RAS) has been previously proposed, but clinical evidence supporting the relationship is incomplete. In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Caron-Debarle et al show that 4 patients with familial partial lipodystrophy associated with early-onset severe hypertension carry mutations in PPARγ that impair its ability to act as a ligand-activated transcription factor. Cells isolated from these patients, and cells transfected with the same mutations in PPARγ, exhibit activation of the cellular RAS, increased production of reactive oxygen species (ROS), and markers of inflammation, all of which are dependent on the angiotensin-II (Ang-II) AT1 receptor (AT1R). This translational study further supports a role for PPARγ as a regulator of blood pressure through its ability to modulate the RAS. See accompanying article on page 829 PPARγ is a ligand-activated transcription factor and target of the thiazolidinedione (TZD) class of antidiabetes mellitus medications. PPARγ is best recognized for its role in adipogenesis, but is also a regulator of systemic metabolism as evidenced by the pleiotropic abnormalities (lipodystrophy, insulin-resistance, and metabolic syndrome) caused by PPARγ mutations.1–3 Clinical studies of TZD use in type 2 diabetes mellitus, including the PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) trial, documented improved endothelial function and modest, but significant reductions in blood pressure.4 Some of the same mutations that cause lipodystrophy and diabetes mellitus also cause severe hypertension and preeclampsia in human patients3 and in knock-in mice.5,6 Evidence suggests that PPARγ activity in the vascular endothelium and smooth muscle are important regulators of endothelial function, smooth muscle contraction, and systemic blood pressure.7,8 Data suggesting a role for PPARγ in regulating blood pressure led many to search for downstream …

The world pandemic of vitamin D deficiency could possibly be explained by cellular inflammatory response activity induced by the renin-angiotensin system

This review attempts to show that there may be a relationship between inflammatory processes induced by chronic overstimulation of the renin-angiotensin system (RAS) and the worldwide deficiency of vitamin D (VitD) and that both disorders are probably associated with environmental factors. Low VitD levels represent a risk factor for several apparently different diseases, such as infectious, autoimmune, neurodegenerative, and cardiovascular diseases, as well as diabetes, osteoporosis, and cancer. Moreover, VitD insufficiency seems to predispose to hypertension, metabolic syndrome, left ventricular hypertrophy, heart failure, and chronic vascular inflammation. On the other hand, inappropriate stimulation of the RAS has also been associated with the pathogenesis of hypertension, heart attack, stroke, and hypertrophy of the left ventricle and vascular smooth muscle cells. Because VitD receptors (VDRs) and RAS receptors are almost distributed in the same tissues, a possible link between VitD and the RAS is even more plausible. Furthermore, from an evolutionary point of view, both systems were developed simultaneously, actively participating in the regulation of inflammatory and immunological mechanisms. Changes in RAS activity and activation of the VDR seem to be inversely related; thus any changes in one of these systems would have a completely opposite effect on the other, making it possible to speculate that the two systems could have a feedback relationship. In fact, the pandemic of VitD deficiency could be the other face of increased RAS activity, which probably causes lower activity or lower levels of VitD. Finally, from a therapeutic point of view, the combination of RAS blockade and VDR stimulation appears to be more effective than either RAS blockade or VDR stimulation individually.

Renin Inhibition and AT1R blockade improve metabolic signaling, oxidant stress and myocardial tissue remodeling

ObjectiveStrategies that block angiotensin II actions on its angiotensin type 1 receptor or inhibit actions of aldosterone have been shown to reduce myocardial hypertrophy and interstitial fibrosis in states of insulin resistance. Thereby, we sought to determine if combination of direct renin inhibition with angiotensin type 1 receptor blockade in vivo, through greater reductions in systolic blood pressure (SBP) and aldosterone would attenuate left ventricular hypertrophy and interstitial fibrosis to a greater extent than either intervention alone. Materials/MethodsWe utilized the transgenic Ren2 rat which manifests increased tissue expression of murine renin which, in turn, results in increased renin–angiotensin system activity, aldosterone secretion and insulin resistance. Ren2 rats were treated with aliskiren, valsartan, the combination (aliskiren+valsartan), or vehicle for 21days. ResultsCompared to Sprague–Dawley controls, Ren2 rats displayed increased systolic blood pressure, elevated serum aldosterone levels, cardiac tissue hypertrophy, interstitial fibrosis and ultrastructural remodeling. These biochemical and functional alterations were accompanied by increases in the NADPH oxidase subunit Nox2 and 3-nitrotyrosine content along with increases in mammalian target of rapamycin and reductions in protein kinase B phosphorylation. Combination therapy contributed to greater reductions in systolic blood pressure and serum aldosterone but did not result in greater improvement in metabolic signaling or markers of oxidative stress, fibrosis or hypertrophy beyond either intervention alone. ConclusionsThereby, our data suggest that the greater impact of combination therapy on reductions in aldosterone does not translate into greater reductions in myocardial fibrosis or hypertrophy in this transgenic model of tissue renin overexpression.

Losartan abolished hyperglycemic effect of chronic mild and unpredictable stress in rats

We've shown previously that chronic mild and unpredictable stress (CMUS) induced endothelium dysfunction and increased renin‐angiotensin system (RAS) activity in rats. Since endothelial dysfunction and high RAS activity has been associated with insulin resistance the aim of this study was to evaluate the effect of losartan on the response to oral glucose tolerance test (OGTT) of rats submitted to CMUS. Male Sprague‐Dawley rats were divided into four groups: control, CMUS, losartan (50mg/Kg) and CMUS + losartan (n=12/group). CMUS protocol consisted in applying different stressor stimuli (immobilization, overnight illumination, water and food deprivation, wed bedding and reversed light/dark cycle) 7 days/wk during three consecutive weeks (from the 3rd to 5th wk) of the experimental protocol, 7 weeks long. OGTT has been performed one week after CMUS. Data were analysed by ANOVA bifatorial (p&lt;0.05). All procedures were approved by Institutional Ethics Committee. CMUS and CMUS+losartan groups presented higher corticosterone plasma level in comparison with non stressed groups. CMUS group presented higher area under the curve of glucose during OGTT in comparison with control group (885,2 ± 10,07 vs. 754,4 ± 16,08 mmol x min/L), without difference between losartan (745,9 ± 15,40) and CMUS+losartan group (816,4 ± 17,01 mmol x min/L). These data show that increased RAS activity is involved in the CMUS hyperglycemia.

Inflammation and Hypertension: The Interplay of Interleukin-6, Dietary Sodium, and the Renin-Angiotensin System in Humans

Prior evidence suggests a link between inflammation and hypertension. Interleukin-6 (IL-6) has been implicated in animal studies to play an important role in angiotensin II (ANGII)-mediated hypertension. The aim of this study was to examine the relationship of IL-6 and renin-angiotensin system (RAS) activity in human hypertension. Data from 385 hypertensives and 196 normotensives are included in this report. Blood pressure and laboratory evaluation were performed on liberal and low sodium diets. IL-6 response to an ANGII infusion was evaluated to assess the effect of acute RAS activation. Hypertensives had higher baseline IL-6 and C-reactive protein (CRP) compared with normotensives on both diets. IL-6 increased in response to ANGII in hypertensives and normotensives (28% in hypertensives, 31% in normotensives, P ≤ 0.001 for change from baseline). In the setting of RAS activation by a low salt diet, multivariate regression analysis adjusted for age, body mass index (BMI), gender, race, and hypertension status demonstrated an independent positive association of plasma renin activity (PRA) with CRP (β = 0.199, P < 0.001). There was no significant difference in IL-6 or CRP levels between liberal and low sodium diets. These findings confirm an association between hypertension and inflammation and provide human data supporting previous evidence from animal studies that IL-6 plays a role in ANGII-mediated hypertension. Notably, compared to levels on a liberal sodium diet, neither IL-6 nor CRP were higher with activation of the RAS by a low salt diet indicating that a low sodium diet is not inflammatory despite increased RAS activity.

Renin-angiotensin system activity in vitamin D deficient, obese individuals with hypertension: An urban Indian study

Background:Elevated renin–angiotensin–aldosterone system (RAAS) activity is an important mechanism in the development of hypertension. Both obesity and 25-hydroxy vitamin D [25(OH)D] deficiency have been associated with hypertension and augmented renin-angiotensin system (RAS) activity. We tried to test the hypothesis that vitamin D deficiency and obesity are associated with increased RAS activity in Indian patients with hypertension.Materials and Methods:Fifty newly detected hypertensive patients were screened. Patients with secondary hypertension, chronic kidney disease, or coronary artery disease were excluded. Patients underwent measurement of vitamin D and plasma renin and plasma aldosterone concentrations. They were divided into three groups according to their baseline body mass index (BMI; normal <25 kg/m2, overweight 25–29.9 kg/m2 and obese ≥30 kg/m2) and 25(OH)D levels (deficient <20 ng/ml, insufficient 20–29 ng/ml and optimal ≥30 ng/ml).Results:A total of 50 (male:female – 32:18) patients were included, with a mean age of 49.5 ± 7.8 years, mean BMI of 28.3 ± 3.4 kg/m2 and a mean 25(OH)D concentration of 18.5 ± 6.4 ng/ml. Mean systolic blood pressure (SBP) was 162.4 ± 20.2 mm Hg and mean diastolic blood pressure (DBP) was 100.2 ± 11.2 mm Hg. All the three blood pressure parameters [SBP, DBP and mean arterial pressure (MAP)] were significantly higher among individuals with lower 25(OH)D levels. The P values for trends in SBP, DBP and MAP were 0.009, 0.01 and 0.007, respectively. Though all the three blood pressure parameters (SBP, DBP and MAP) were higher among individuals with higher BMIs, they were not achieving statistical significance. Increasing trends in PRA and PAC were noticed with lower 25(OH)D and higher BMI levels.Conclusion:Vitamin D deficiency and obesity are associated with stimulation of RAAS activity. Vitamin D supplementation along with weight loss may be studied as a therapeutic strategy to reduce tissue RAS activity in individualswith Vitamin D deficiency and obesity.