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1.  Association of Leukocyte Telomere Length with Circulating Biomarkers of the Renin-Angiotensin-Aldosterone System: The Framingham Heart Study 
Circulation  2008;117(9):1138-1144.
Leucocyte telomere length (LTL) chronicles the cumulative burden of oxidative stress and inflammation over a life course. Activation of the renin-angiotensin-aldosterone system (RAAS) is associated with increased oxidative stress and inflammation. Therefore, LTL may be related to circulating biomarkers of the RAAS.
We evaluated the cross-sectional relations of LTL (dependent variable) to circulating renin and aldosterone concentrations and the renin-aldosterone ratio (all logarithmically-transformed; independent variables) in 1203 Framingham Study participants (mean age 59 years, 51% women). We used multivariable linear regression and adjusted for age, blood pressure, hypertension treatment, smoking, diabetes, body mass index, hormone replacement therapy, serum creatinine and the urine sodium-creatinine ratio.
Overall, multivariable-adjusted LTL was inversely related to renin (beta coefficient per unit increase [β]=-0.038; p= 0.036), directly related to aldosterone (β=0.099; p= 0.002), and inversely related to the renin-aldosterone ratio (β=-0.049; p= 0.003). Relations of LTL to biomarkers were stronger in those with hypertension, although a formal test of interaction was not statistically significant (p=0.20). Individuals with hypertension displayed significant associations of LTL with renin (β=-0.060; p= 0.005), aldosterone (β=0.134; p= 0.002) and renin-aldosterone ratio (β=-0.072; p<0.001). Participants with hypertension who were in the top tertile of the renin-aldosterone ratio had LTL that was 182 base pairs shorter relative to those in the lowest tertile.
In our community-based sample, LTL was shorter in individuals with a higher renin-aldosterone ratio, especially so in participants with hypertension. Additional investigations are warranted to confirm our observations.
PMCID: PMC3142671  PMID: 18268147
Telomere; Renin; Aldosterone; Hypertension; Epidemiology; Association; Salt; Oxidative stress
2.  Relations of Biomarkers Representing Distinct Biological Pathways to Left Ventricular Geometry 
Circulation  2008;118(22):2252-2258.
Several biological pathways are activated concomitantly during left ventricular (LV) remodeling. However, the relative contribution of circulating biomarkers representing these distinct pathways to LV geometry is unclear.
Methods and Results
We evaluated 2119 Framingham Offspring Study participants (mean age 57 years; 57% women) who underwent measurements of biomarkers of inflammation (C-reactive protein, CRP), hemostasis (fibrinogen; plasminogen activator inhibitor 1, PAI-1), neurohormonal activation (B-type natriuretic peptide, BNP); renin-angiotensin-aldosterone system ([RAAS], aldosterone and renin modeled as a ratio, ARR), and echocardiography at a routine examination. LV geometry was defined based on sex-specific distributions of LV mass (LVM) and relative wall thickness (RWT): normal (LVM and RWT<80th percentile), concentric remodeling (LVM
Modeled individually, CRP, fibrinogen, PAI-1 and ARR were related to LV geometry (p<0.01). In multivariable analyses, the biomarker panel was significantly related to altered LV geometry (p<0.0001). Upon backwards elimination, logARR alone was significantly and positively associated with eccentric (odds ratio [OR] per standard deviation (SD) increment 1.20; 95% CI 1.05-1.37) and concentric LV hypertrophy (OR per SD increment 1.29; 95% CI 1.06-1.58).
Our cross-sectional observations on a large community-based sample identified ARR as a key correlate of concentric and eccentric LV hypertrophy, consistent with a major role for RAAS in LV remodeling.
PMCID: PMC2747641  PMID: 19001021
epidemiology; ventricular hypertrophy; biomarkers; ventricular remodeling; renin angiotensin system; aldosterone; c-reactive protein; PAI-1; fibrinogen
Heart  2000;83(3):257-261.
BACKGROUND—It remains uncertain whether angiotensin converting enzyme (ACE) inhibitors benefit all heart failure patients or just those with renin-angiotensin-aldosterone system (RAAS) activation.
OBJECTIVE—To determine whether the response to an ACE inhibitor, assessed by urine sodium excretion, was different in patients with low renin versus those with high renin.
DESIGN—Plasma renin activity (PRA) was measured in 38 patients with stable chronic heart failure (21 male, 17 female; mean (SD) age 71 (6) years, range 59-82 years) on chronic diuretic treatment alone. They were divided into three groups: low (PRA ⩽ 1.5 ng/ml/h, n = 11); normal (1.5 < PRA < 5, n = 14); and high (PRA > 5, n = 13). The effect of ACE inhibition was then assessed on diuretic induced natriuresis with respect to renin status.
RESULTS—There were no significant differences in age and sex distribution between the groups. Plasma angiotensin II and aldosterone increased serially from low to high renin groups, while 24 h urinary sodium concentrations fell from low to high renin groups (low PRA, 96.7 (39.5); normal PRA, 90.4 (26.7); high PRA, 66.3 (18.9) mmol/l; p = 0.033), despite a higher diuretic dose in the high renin group. This blunted natriuretic effect of loop diuretics was caused by RAAS activation, which could partly be reversed by ACE inhibition. ACE inhibitors increased natriuresis by 22% in the high renin group (p = 0.029), but had no effect in the normal and low renin groups. Within the low renin group, five of the 11 patients had persistently low renin levels despite ACE inhibition. There was a non-significant reduction in natriuresis (−9.6%, p = 0.335) following ACE inhibition in this subgroup of patients.
CONCLUSIONS—About one third of heart failure patients in our study had low renin status and a non-activated RAAS, despite diuretic treatment. ACE inhibitors did not alter natriuresis significantly in this subgroup of patients, and enhanced natriuresis only in patients with high renin. There is thus tentative support for renin profiling in targeting ACE inhibitors to the most deserving, by showing that short term sodium retention does not occur in low renin patients if ACE inhibitors are withdrawn.

Keywords: chronic heart failure; renin profiling; ACE inhibition; urinary sodium excretion
PMCID: PMC1729351  PMID: 10677399
Current Hypertension Reports  2012;14(2):160-169.
Obesity is a risk factor for type 2 diabetes mellitus (DM) and is associated with chronic kidney disease. Activation of the renin-angiotensin-aldosterone system (RAAS) is common in obesity. The RAAS is an important mediator of hypertension. Mechanisms involved in activation of the RAAS in obesity include sympathetic stimulation, synthesis of adipokines in the RAAS by visceral fat, and hemodynamic alterations. The RAAS is known for its role in regulating blood pressure and fluid and electrolyte homeostasis. The role of local/tissue RAAS in specific tissues has been a focus of research. Urinary angiotensinogen (UAGT) provides a specific index of the intrarenal RAAS. Investigators have demonstrated that sex steroids can modulate the expression and activity of the different components of the intrarenal RAAS and other tissues. Our data suggest that obese women without DM and hypertension have significantly higher levels of UAGT than their male counterparts. These differences existed without any background difference in the ratio of microalbumin to creatinine in the urine or the estimated glomerular filtration rate, raising a question about the importance of baseline gender differences in the endogenous RAAS in the clinical spectrum of cardiovascular diseases and the potential utility of UAGT as a marker of the intrarenal RAAS. Animal studies have demonstrated that modifying the amount of angiotensin, the biologically active component of the RAAS, directly influences body weight and adiposity. This article reviews the role of the RAAS in renal injury seen in obesity and the metabolic syndrome.
PMCID: PMC3337881  PMID: 22302531
Renin-angiotensin-aldosterone system; RAAS; Renin-angiotensin system; Renal injury; Angiotensinogen; UAGT; Obesity; Metabolic syndrome; Chronic kidney disease; Diabetes mellitus; Gender differences; Hypertension; Blood pressure; Urine; Clinical study
Kidney international  2013;85(2):404-415.
The level of the renin-angiotensin-aldosterone system (RAAS) activity in kidney transplant recipients has not been extensively studied or serially profiled. To describe this axis and to determine its association with GFR change, interstitial expansion and end-stage renal disease (ESRD) we measured plasma renin activity (PRA) and plasma aldosterone levels annually for 5 years in 153 kidney transplant recipients randomly assigned to losartan or placebo. PRA and plasma aldosterone levels were in the normal range at all times and did not vary by immunosuppression regimen. Those on losartan exhibited higher PRA but similar plasma aldosterone levels. Neither baseline nor serial PRA or plasma aldosterone levels were associated with GFR decline, proteinuria or interstitial expansion. Losartan use, [HR 0.48 (95% CI 0.21–1.0), insignificant], and Caucasian donor, [HR 0.18 (95% CI 0.07–0.4), significant] were associated with less doubling of serum creatinine, death or ESRD. Hypertension, less than 3 HLA-matches, the combination of tacrolimus-rapamycin and acute rejection were associated with more events. Neither PRA nor plasma aldosterone levels were independently associated with this outcome. Higher serial plasma aldosterone levels were associated, however, with a significantly higher risk of ESRD, [HR 1.01 (95% CI 1.00–1.02)]. Thus, systemic RAAS is not overly activated in kidney transplant recipients but this may not reflect the intrarenal system. Importantly, plasma aldosterone levels may be associated with more ESRD.
PMCID: PMC3946607  PMID: 23965522
Clinical endocrinology  2011;74(3):294-299.
Both resistin and vitamin D have been associated with the renin-angiotensin-aldosterone system (RAAS). We investigated the association between resistin and the RAAS, and resistin and vitamin D under controlled dietary sodium conditions.
Retrospective cross-sectional study of subjects from the HyperPATH Consortium, who were maintained in high dietary sodium (HS) and low dietary sodium (LS) balance for one week each.
Caucasian subjects with hypertension (n=177).
25-hydroxyvitamin D (25[OH]D) levels were used to assess vitamin D status. Plasma resistin and RAAS measures were evaluated on each dietary intervention.
Resistin levels were significantly higher in LS, where RAAS activity was high, when compared to HS balance, where RAAS activity was suppressed (6.36 vs. 5.86 µg/L, p<0.0001); however, resistin concentrations were not associated with plasma renin activity or serum aldosterone on either diet. 25(OH)D levels were positively and independently associated with resistin in both dietary conditions (HS: β=0.400, p-trend=0.027; LS: β=0.540, p-trend=0.014).
Dietary sodium loading reduced resistin levels, possibly by suppressing the RAAS; however, circulating RAAS components were not related to resistin concentrations within each specific dietary sodium condition. 25(OH)D was positively associated with resistin and may be involved in resistin regulation through an unknown mechanism. Further studies to better understand resistin regulation in human hypertension are warranted.
PMCID: PMC3059847  PMID: 21050256
resistin; renin; angiotensin; sodium; vitamin D
Postural tachycardia syndrome (POTS) is a disorder characterized by excessive orthostatic tachycardia and significant functional disability. Previously, we reported that POTS patients have low blood volume and inappropriately low renin activity (PRA) and aldosterone. In this study, we sought to more fully characterize the renin-angiotensin-aldosterone system (RAAS), to gain a better understanding of the pathophysiology of POTS.
We prospectively assessed the plasma levels of Angiotensin (Ang) peptides and their relationship to other RAAS components in patients with POTS compared with healthy controls.
While on a sodium controlled diet, heart rate (HR), PRA, Ang I, Ang II, Ang (1–7) and aldosterone were measured in POTS patients (n=38) and healthy controls (n=13).
POTS patients had larger orthostatic increases in HR than controls (52±3 [mean±SEM] bpm vs. 27±6 bpm; P=0.001). Plasma Ang II was significantly higher in POTS patients (43±3 pg/ml vs. 28±3 pg/ml; P=0.006), while plasma Ang I and Ang-(1–7) were similar between groups. Despite the two-fold increase of Ang II, POTS patients trended to lower PRA levels than controls (0.9±0.1 ng/mL/h vs. 1.6±0.5 ng/mL/h, P=0.268) and lower aldosterone levels (4.6±0.8 pg/ml vs. 10.0±3.0 pg/ml; P=0.111). Estimated angiotensin-converting enzyme-2 (ACE2) activity was significantly lower in POTS than controls (0.25±0.02 vs. 0.33±0.03; P=0.038).
Some patients with POTS have inappropriately high plasma angiotensin II levels, with low estimated ACE2 activity. We propose that these abnormalities in angiotensin regulation may play a key role in the pathophysiology of POTS in some patients.
PMCID: PMC3050076  PMID: 21266211
tachycardia; autonomic nervous system; angiotensin II; aldosterone; ACE2
Prior studies have suggested that circulating adiponectin concentrations are associated positively with vitamin D and negatively with body-mass index (BMI), but have not accounted for the influence of the renin-angiotensin-aldosterone system (RAAS) in this relationship. This is particularly relevant because increased RAAS activity is associated with obesity and is known to lower adiponectin levels. We evaluated the association between adiponectin and 25-hydroxyvitamin D (25[OH]D) after controlling RAAS activity with dietary sodium equilibration, and also evaluated whether this relationship was influenced by BMI.
Cross-sectional study of 115 hypertensive Caucasian men from the HyperPATH Consortium.
To manipulate RAAS activity, all subjects underwent one week of high sodium (HS) diet to suppress RAAS, and one week of low sodium (LS) diet to stimulate RAAS. Linear regression was used to evaluate the association between adiponectin and 25(OH)D, and the effect of BMI on this relationship, in each dietary condition.
Adiponectin was higher on HS, where circulating RAAS activity was low, when compared to LS (HS=2.9 versus LS=2.4 µg/mL, p<0.0001). 25(OH)D levels were positively associated with adiponectin, and BMI was a statistically significant effect modifier of the relationship between 25(OH)D and adiponectin on both diets (p-interaction < 0.01 between BMI and 25[OH]D).
Higher 25(OH)D concentrations were independently associated with higher adiponectin levels, particularly when BMI was high. Dietary sodium balance and circulating RAAS activity did not appear to affect this relationship. Future studies should explore whether vitamin D supplementation increases adiponectin levels in obesity.
PMCID: PMC3104074  PMID: 21402748
PLoS ONE  2013;8(7):e68908.
Patients with type 1 diabetes mellitus (DM) and renal hyperfiltration also exhibit systemic microvascular abnormalities, including endothelial dysfunction. The effect of renal hyperfiltration on systemic blood pressure (BP) is less clear. We therefore measured BP, renal hemodynamic function and circulating renin angiotensin aldosterone system (RAAS) mediators in type 1 DM patients with hyperfiltration (n = 36, DM-H, GFR≥135 ml/min/1.73 m2) or normofiltration (n = 40, DM-N), and 56 healthy controls (HC). Since renal hyperfiltration represents a state of intrarenal RAAS activation, we hypothesized that hyperfiltration would be associated with higher BP and elevated levels of circulating RAAS mediators.
BP, glomerular filtration rate (GFR - inulin), effective renal plasma flow (paraaminohippurate) and circulating RAAS components were measured in DM-H, DM-N and HC during clamped euglycemia (4–6 mmol/L). Studies were repeated in DM-H and DM-N during clamped hyperglycemia (9–11 mmol/L).
Baseline GFR was elevated in DM-H vs. DM-N and HC (167±6 vs. 115±2 and 115±2 ml/min/1.73 m2, p<0.0001). Baseline systolic BP (SBP, 117±2 vs. 111±2 vs. 109±1, p = 0.004) and heart rate (76±1 vs. 67±1 vs. 61±1, p<0.0001) were higher in DM-H vs. DM-N and HC. Despite higher SBP in DM-H, plasma aldosterone was lower in DM-H vs. DM-N and HC (42±5 vs. 86±14 vs. 276±41 ng/dl, p = 0.01). GFR (p<0.0001) and SBP (p<0.0001) increased during hyperglycemia in DM-N but not in DM-H.
DM-H was associated with higher heart rate and SBP values and an exaggerated suppression of systemic aldosterone. Future work should focus on the mechanisms that explain this paradox in diabetes of renal hyperfiltration coupled with systemic RAAS suppression.
PMCID: PMC3701674  PMID: 23861950
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).
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.
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.
PMCID: PMC3230105  PMID: 22145146
Hypertension; obesity; renin–angiotensin–aldosterone system; vitamin D
Current hypertension reports  2013;15(1):59-70.
Alterations in the renin angiotensin aldosterone system (RAAS) contribute to the underlying pathophysiology of insulin resistance in humans; however, individual differences in the treatment response of insulin resistance to RAAS blockade persist. Thus, understanding inter-individual differences in the relationship between the RAAS and insulin resistance may provide insights into improved personalized treatments and improved outcomes. The effects of the systemic RAAS on blood pressure regulation and glucose metabolism have been studied extensively; however, recent discoveries on the influence of local tissue RAAS in the skeletal muscle, heart, vasculature, adipocytes, and pancreas have led to an improved understanding of how activated tissue RAAS influences the development of insulin resistance and diabetes in humans. Angiotensin II (ANGII) is the predominant RAAS component contributing to insulin resistance; however, other players such as aldosterone, renin, and ACE2 are also involved. This review examines the role of local ANGII activity on insulin resistance development in skeletal muscle, adipocytes, and pancreas, followed by a discussion of the other RAAS components implicated in insulin resistance, including ACE2, Ang1-7, renin, and aldosterone.
PMCID: PMC3551270  PMID: 23242734
Renin angiotensin aldosterone system; Angiotensin II; Insulin resistance; Aldosterone; Insulin signaling; Angiotensin converting enzyme; Angiotensin 1-7; Diabetes mellitus; Glucose metabolism; Skeletal muscle; Adipocytes; Pancreas; Insulin secretion; Inflammation; Genetics; Polymorphisms; Angiotensin II receptor blocker; Angiotensin converting enzyme inhibitor; Insulin sensitivity; Human studies; Animal models; Renin inhibitor; Obesity; Hypertension; Clinical trials
Combination therapy is necessary for most patients with hypertension, and agents that inhibit the renin-angiotensin-aldosterone system (RAAS) are mainstays in hypertension management, especially for patients at high cardiovascular and renal risk. Single blockade of the RAAS with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) confers some cardiorenal protection; however, these agents do not extinguish the RAAS as evidenced by a reactive increase in plasma renin activity (PRA), a cardiovascular risk marker, and incomplete cardiorenal protection. Dual blockade with an ACE inhibitor and an ARB offers no additional benefit in patients with hypertension and normal renal and left ventricular function. Indeed, PRA increases synergistically with dual blockade. Aliskiren, the first direct renin inhibitor (DRI) to become available has provided an opportunity to study the merit of DRI/ARB combination treatment. By blocking the first and rate-limiting step in the RAAS, aliskiren reduces PRA by at least 70% and buffers the compensatory increase in PRA observed with ACE inhibitors and ARBs. The combination of a DRI and an ARB or an ACE inhibitor is an effective approach for lowering blood pressure; available data indicate that such combinations favorably affect proteinuria, left ventricular mass index, and brain natriuretic peptide in patients with albuminuria, left ventricular hypertrophy, and heart failure, respectively. Ongoing outcome studies will clarify the role of aliskiren and aliskiren-based combination RAAS blockade in patients with hypertension and those at high cardiorenal risk.
PMCID: PMC2941784  PMID: 20859542
aliskiren; valsartan; single-pill combination; hypertension; renin-angiotensin-aldosterone system; plasma renin activity
Objective. To observe the relationship between changes in renin-angiotensin-aldosterone system (RAAS) activity and blood plasma glucose after administration of hydrochlorothiazide (HCTZ) for one year in patients with hypertension. Methods. 108 hypertensive patients were given 12.5 mg HCTZ per day for one year. RAAS activity, plasma glucose levels, and other biochemical parameters, as well as plasma oxidized low density lipoprotein (oxLDL) levels, were measured and analyzed at baseline, six weeks, and one year after treatment. Results. After one year of treatment, the reduction in plasma glucose observed between the elevated plasma renin activity (PRA) group (−0.26 ± 0.26 mmol/L) and the nonelevated PRA group (−1.36 ± 0.23 mmol/L) was statistically significant (P < 0.05). The decrease of plasma glucose in the elevated Ang II group (−0.17 ± 0.18 mmol/L) compared to the nonelevated Ang II group (−1.07 ± 0.21 mmol/L) was statistically significant (P < 0.05). The proportion of patients with elevated plasma glucose in the elevated Ang II group (40.5%) was significantly higher than those in the nonelevated Ang II group (16.3%) (P < 0.05). The relative oxLDL level was not affected by the treatment. Conclusions. Changes in RAAS activity were correlated with changes in plasma glucose levels after one year of HCTZ therapy.
PMCID: PMC3852583  PMID: 24349612
BMC Psychiatry  2003;3:15.
Hypercortisolism as a sign of hypothamamus-pituitary-adrenocortical (HPA) axis overactivity and sleep EEG changes are frequently observed in depression. Closely related to the HPA axis is the renin-angiotensin-aldosterone system (RAAS) as 1. adrenocorticotropic hormone (ACTH) is a common stimulus for cortisol and aldosterone, 2. cortisol release is suppressed by mineralocorticoid receptor (MR) agonists 3. angiotensin II (ATII) releases CRH and vasopressin from the hypothalamus. Furthermore renin and aldosterone secretion are synchronized to the rapid eyed movement (REM)-nonREM cycle.
Here we focus on the difference of sleep related activity of the RAAS between depressed patients and healthy controls. We studied the nocturnal plasma concentration of ACTH, cortisol, renin and aldosterone, and sleep EEG in 7 medication free patients with depression (1 male, 6 females, age: (mean +/-SD) 53.3 ± 14.4 yr.) and 7 age matched controls (2 males, 5 females, age: 54.7 ± 19.5 yr.). After one night of accommodation a polysomnography was performed between 23.00 h and 7.00 h. During examination nights blood samples were taken every 20 min between 23.00 h and 7.00 h. Area under the curve (AUC) for the hormones separated for the halves of the night (23.00 h to 3.00 h and 3.00 h to 7.00 h) were used for statistical analysis, with analysis of co variance being performed with age as a covariate.
No differences in ACTH and renin concentrations were found. For cortisol, a trend to an increase was found in the first half of the night in patients compared to controls (p < 0.06). Aldosterone was largely increased in the first (p < 0.05) and second (p < 0.01) half of the night. Cross correlations between hormone concentrations revealed that in contrast to earlier findings, which included only male subjects, in our primarily female sample, renin and aldosterone secretion were not coupled and no difference between patients and controls could be found, suggesting a gender difference in RAAS regulation. No difference in conventional sleep EEG parameters were found in our sample.
Hyperaldosteronism could be a sensitive marker for depression. Further our findings point to an altered renal mineralocorticoid sensitivity in patients with depression.
PMCID: PMC280657  PMID: 14585110
Heart Failure Reviews  2011;17(2):191-201.
The renin-angiotensin-aldosterone-system (RAAS) plays a central role in the pathophysiology of heart failure and cardiorenal interaction. Drugs interfering in the RAAS form the pillars in treatment of heart failure and cardiorenal syndrome. Although RAAS inhibitors improve prognosis, heart failure–associated morbidity and mortality remain high, especially in the presence of kidney disease. The effect of RAAS blockade may be limited due to the loss of an inhibitory feedback of angiotensin II on renin production. The subsequent increase in prorenin and renin may activate several alternative pathways. These include the recently discovered (pro-) renin receptor, angiotensin II escape via chymase and cathepsin, and the formation of various angiotensin subforms upstream from the blockade, including angiotensin 1–7, angiotensin III, and angiotensin IV. Recently, the direct renin inhibitor aliskiren has been proven effective in reducing plasma renin activity (PRA) and appears to provide additional (tissue) RAAS blockade on top of angiotensin-converting enzyme and angiotensin receptor blockers, underscoring the important role of renin, even (or more so) under adequate RAAS blockade. Reducing PRA however occurs at the expense of an increase plasma renin concentration (PRC). PRC may exert direct effects independent of PRA through the recently discovered (pro-) renin receptor. Additional novel possibilities to interfere in the RAAS, for instance using vitamin D receptor activation, as well as the increased knowledge on alternative pathways, have revived the question on how ideal RAAS-guided therapy should be implemented. Renin and prorenin are pivotal since these are at the base of all of these pathways.
PMCID: PMC3310995  PMID: 21695549
Heart failure; Renin; Prorenin; Cardiorenal
The renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathogenesis of cardiovascular disorders including hypertension and is one of the most important targets for drugs. A whole body physiologically based pharmacokinetic (wb PBPK) model integrating this hormone circulation system and its inhibition can be used to explore the influence of drugs that interfere with this system, and thus to improve the understanding of interactions between drugs and the target system. In this study, we describe the development of a mechanistic RAAS model and exemplify drug action by a simulation of enalapril administration. Enalapril and its metabolite enalaprilat are potent inhibitors of the angiotensin-converting-enzyme (ACE). To this end, a coupled dynamic parent-metabolite PBPK model was developed and linked with the RAAS model that consists of seven coupled PBPK models for aldosterone, ACE, angiotensin 1, angiotensin 2, angiotensin 2 receptor type 1, renin, and prorenin. The results indicate that the model represents the interactions in the RAAS in response to the pharmacokinetics (PK) and pharmacodynamics (PD) of enalapril and enalaprilat in an accurate manner. The full set of RAAS-hormone profiles and interactions are consistently described at pre- and post-administration steady state as well as during their dynamic transition and show a good agreement with literature data. The model allows a simultaneous representation of the parent-metabolite conversion to the active form as well as the effect of the drug on the hormone levels, offering a detailed mechanistic insight into the hormone cascade and its inhibition. This model constitutes a first major step to establish a PBPK-PD-model including the PK and the mode of action (MoA) of a drug acting on a dynamic RAAS that can be further used to link to clinical endpoints such as blood pressure.
PMCID: PMC3567458  PMID: 23404365
physiologically based pharmacokinetic model; cardiovascular; renin-angiotensin-aldosterone system; enalapril; enalaprilat
Diabetes, obesity & metabolism  2012;15(1):28-34.
The renin-angiotensin-aldosterone system (RAAS) and autonomic nervous system regulate the cardiovascular system. Blockade of the RAAS may slow progression of end-organ damage. Direct renin inhibition offers a means for blocking the RAAS. The objective of this study was to examine the effect of direct renin inhibition on cardiovascular autonomic function.
In this double-blind, placebo-controlled trial, 60 individuals with diabetes were randomly assigned to 300 mg of aliskiren or placebo once daily for 6 weeks. The primary end point was a change in tests of cardiovascular autonomic function. Autonomic function was assessed by power spectral analysis and RR-variation during deep breathing (i.e., mean circular resultant (MCR), expiration/inspiration (E/I) ratio). The MCR and E/I ratio assess parasympathetic function. Secondary measures included change in biochemical parameters (e.g., plasma renin activity, leptin, interleukin-6). Change in cardiovascular autonomic function and blood analytes were analyzed by a mixed effects model for repeated measures.
Baseline characteristics were similar between treatment groups. In response to aliskiren compared with placebo, blood pressure was reduced as well as plasma renin activity (from 2.4±3.8 (mean±SD) to 0.5±0.4 μg/l/h, p<0.001). There was a significant interaction (aliskiren x visit) for MCR (p=0.003) and E/I ratio (p=0.003) indicating improvement in MCR and E/I ratio for those on aliskiren. MCR means, baseline vs. follow-up, were 41.8±19.7 vs. 50.8±26.1 (aliskiren) and 38.2±23.6 vs. 37.5±24.1 (placebo).
Parasympathetic function (i.e., MCR and E/I ratio) was enhanced by down-regulation of the RAAS.
PMCID: PMC3524360  PMID: 22834767
Cardiovascular autonomic function; renin-angiotensin-aldosterone system; renin inhibition; parasympathetic function
American heart journal  2012;164(5):10.1016/j.ahj.2012.08.014.
Acute decompensated heart failure (ADHF) occurs with preserved (HFpEF, EF≥50%) or reduced (HFrEF, EF<50%) ejection fraction. Natriuretic peptide (NP) levels are lower in HFpEF than HFrEF. We hypothesized that lower NP levels in HFpEF may be associated with other differences in biomarkers; specifically, renin-angiotensin-aldosterone system (RAAS) activation, oxidative stress and a biomarker that reflects collagen synthesis.
In this pre-specified ancillary analysis of ADHF patients enrolled in the Diuretic Optimization Strategies Evaluation (DOSE) study, clinical features and NT-proBNP, cystatin C, plasma renin activity (PRA), aldosterone, oxidative stress (uric acid) and procollagen type III N-terminal peptide (PIIINP) were compared in HFpEF and HFrEF at enrollment and 60 day follow-up.
Compared to HFrEF (n=219), HFpEF (n=81) patients were older, heavier, more commonly female, less treated with RAAS antagonists, but with similar NYHA class, jugular venous pressure and edema severity. NT-proBNP was lower and systolic blood pressure (BP) and cystatin C were higher in HFpEF. Despite higher systolic BP and less RAAS antagonist use in HFpEF, PRA and aldosterone levels were similar in HFpEF and HFrEF as were uric acid and PIIINP levels. Changes in biomarker levels from enrollment to 60 days were similar between HFrEF (n=149) and HFpEF (n=50).
Lower NP levels in decompensated HFpEF occur in association with similar ADHF severity, more impaired vascular and renal function but similar elevation of biomarkers that reflect RAAS activation, oxidative stress and collagen synthesis as in HFrEF.
PMCID: PMC3875288  PMID: 23137508
Regulatory Peptides  2012;176(1-3):36-44.
Enhanced renin-angiotensin-aldosterone system (RAAS) activation contributes to proteinuria and chronic kidney disease by increasing glomerular and tubulointerstitial oxidative stress, promotion of fibrosis. Renin activation is the rate limiting step in angiotensin (Ang II) and aldosterone generation, and recent work suggests direct renin inhibition improves proteinuria comparable to that seen with Ang type 1 receptor (AT1R) blockade. This is important as, even with contemporary use of AT1R blockade, the burden of kidney disease remains high. Thereby, we sought to determine if combination direct renin inhibition with AT1R blockade in vivo, via greater attenuation of kidney oxidative stress, would attenuate glomerular and proximal tubule injury to a greater extent than either intervention alone. We utilized the transgenic Ren2 rat with increased tissue RAS activity and higher serum levels of aldosterone, which manifests hypertension and proteinuria. Ren2 rats were treated with renin inhibition (aliskiren), AT1R blockade (valsartan), the combination (aliskiren+valsartan), or vehicle for 21 days. Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic pressure (SBP), circulating aldosterone, proteinuria and greater urine levels of the proximal tubule protein excretory marker beta-N-acetylglucosaminidase (β-NAG). These functional and biochemical alterations were accompanied by increases in kidney tissue NADPH oxidase subunit Rac1 and 3-nitrotyrosine (3-NT) content as well as fibronectin and collagen type III. These findings occurred in conjunction with reductions in the podocyte-specific protein podocin as well as the proximal tubule-specific megalin. Further, in transgenic animals there was increased tubulointerstitial fibrosis on light microscopy as well as ultrastructural findings of glomerular podocyte foot-process effacement and reduced tubular apical endosomal/lysosomal activity. Combination therapy led to greater reductions in SBP and serum aldosterone, but did not result in greater improvement in markers of glomerular and tubular injury (ie. β-NAG) compared to either intervention alone. Further, combination therapy did not improve markers of oxidative stress and podocyte and proximal tubule integrity in this transgenic model of RAAS-mediated kidney damage despite greater reductions in serum aldosterone and BP levels.
PMCID: PMC3348429  PMID: 22465166
Aldosterone; Combination; Renin inhibition; AT1R blockade; Podocyte; β-NAG; Oxidative Stress
Global Cardiology Science & Practice  2013;2013(3):269-278.
The renin-angiotensin-aldosterone system (RAAS) regulates the body's hemodynamic equilibrium, circulating volume, and electrolyte balance, and is a key therapeutic target in hypertension, the world's leading cause of premature mortality. Hypertensive disorders are strongly linked with an overactive RAAS, and RAAS inhibitors, like angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), are routinely used to treat high blood pressure (BP). BP reduction is one of the main goals of current European hypertension guidelines. Oral ACE inhibitors, the oldest category of RAAS inhibitor, were commercially released over 30 years ago in the early 1980s, over a decade before the first ARBs became available. The introduction of ACE inhibitors heralded major changes in the way hypertension and cardiovascular disease were treated. Although the decision of the medical community to replace older ACE inhibitors with more modern ARBs in the 1990s was debatable, it did nevertheless allow scientists to learn more about the angiotensin receptors involved in RAAS stimulation. This and much else of value have been discovered since RAAS inhibitors first became available, but some surprising gaps in our knowledge exist. Until recently, the effect of RAAS inhibition on mortality in hypertension was unknown. This question was recently addressed by a meta-analysis of randomized controlled trials in populations who received contemporary antihypertensive medication. The results of this meta-analysis have helped elucidate the long-term consequences of treatment with RAAS inhibitors on mortality in hypertension. This article will consider the differences between RAAS inhibitors in terms of pharmacological and clinical effects and analyze the impact of the main types of RAAS inhibitor, ACE inhibitors and ARBs, on mortality reduction in hypertensive patients with reference to this latest meta-analysis.
PMCID: PMC3963752  PMID: 24689028
Journal of human hypertension  2012;27(3):176-180.
Serum- and glucocorticoid-inducible kinase 1 (SGK1) plays a central role in epithelial sodium channel (ENaC)-dependent Na+ transport in the distal nephron. We hypothesized that SGK1 gene variants may contribute to the effect of dietary salt intake on BP in humans with hypertension, and consequentially influence renin-angiotensin-aldosterone (RAA) system activity. Our study population included 421 hypertensive Caucasian participants of the HyperPath group who had completed a dietary salt protocol with measurement of BP and RAA system activity. Three SGK1 tagging single nucleotide polymorphisms (SNPs) from the HapMap CEU population captured the genetic variation in the SGK1 region. Assuming an additive genetic model, two SNPs (rs2758151 and rs9402571) were associated with BP and plasma renin activity (PRA) effects of dietary salt intake. Major alleles were associated with higher systolic BP on high salt and decreased PRA on low salt. In contrast, low salt neutralized genotype differences. Similar, non-significant trends were observed in a normotensive population (N=152). Genotype was also associated with two salt-sensitive subtypes of hypertension. SGK1 genetic variants are associated with salt sensitivity of BP and PRA in human hypertension. Genotype status at these SGK1 variants may identify individuals prone to salt-sensitive hypertension.
PMCID: PMC3463709  PMID: 22648267
SGK1; polymorphism; renin; salt sensitivity
Life sciences  2009;86(9-10):289-299.
This article reviews the importance of the renin-angiotensin-aldosterone system (RAAS) in the cardiometabolic continuum; presents the pros and cons of dual RAAS blockade with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs); and examines the theoretical and practical benefits supporting the use of direct renin inhibitors (DRIs) in combination with ACEIs or ARBs.
Main methods
The author reviewed the literature for key publications related to the biochemical physiology of the RAAS and the pharmacodynamic effects of ACEIs, ARBs, and DRIs, with a particular focus on dual RAAS blockade with these drug classes.
Key findings
Although ACEI/ARB combination therapy produces modest improvement in BP, it has not resulted in the major improvements predicted given the importance of the RAAS across the cardiorenal disease continuum. This may reflect the fact that RAAS blockade with ACEIs and/or ARBs leads to exacerbated renin release through loss of negative-feedback inhibition, as well as ACE/aldosterone escape through RAAS and non–RAAS-mediated mechanisms. Plasma renin activity (PRA) is an independent predictor of morbidity and mortality, even for patients receiving ACEIs and ARBs. When used alone or in combination with ACEIs and ARBs, the DRI aliskiren effectively reduces PRA. Reductions in BP are greater with these combinations, relative to the individual components alone.
It is possible that aliskiren plus either an ACEI or ARB may provide greater RAAS blockade than monotherapy with ACEIs or ARBs, and lead to additive improvement in BP and clinically important outcomes.
PMCID: PMC2853260  PMID: 19958778
hypertension; renin-angiotensin-aldosterone system (RAAS) inhibition; angiotensin II; angiotensin-(1–7); combination therapy; aliskiren; prorenin/renin receptor
BMC Medical Genetics  2007;8:27.
The renin-angiotensin-aldosterone system (RAAS) is involved in the cardiovascular homeostasis as shown by previous studies reporting a positive association between specific RAAS genotypes and an increased risk of myocardial infarction. Anyhow the prognostic role in a long-term follow-up has not been yet investigated.
Aim of the study was to evaluate the influence of the most studied RAAS genetic Single Nucleotide Polymorphisms (SNPs) on the occurrence and the long-term prognosis of acute myocardial infarction (AMI) at young age in an Italian population.
The study population consisted of 201 patients and 201 controls, matched for age and sex (mean age 40 ± 4 years; 90.5% males). The most frequent conventional risk factors were smoke (p < 0.001), family history for coronary artery diseases (p < 0.001), hypercholesterolemia (p = 0.001) and hypertension (p = 0.002). The tested genetic polymorphisms were angiotensin converting enzyme insertion/deletion (ACE I/D), angiotensin II type 1 receptor (AGTR1) A1166C and aldosterone synthase (CYP11B2) C-344T. Considering a long-term follow-up (9 ± 4 years) we compared genetic polymorphisms of patients with and without events (cardiac death, myocardial infarction, revascularization procedures).
We found a borderline significant association of occurrence of AMI with the ACE D/I polymorphism (DD genotype, 42% in cases vs 31% in controls; p = 0.056). DD genotype remained statistically involved in the incidence of AMI also after adjustment for clinical confounders.
On the other hand, during the 9-year follow-up (65 events, including 13 deaths) we found a role concerning the AGTR1: the AC heterozygous resulted more represented in the event group (p = 0.016) even if not independent from clinical confounders. Anyhow the Kaplan-Meier event free curves seem to confirm the unfavourable role of this polymorphism.
Polymorphisms in RAAS genes can be important in the onset of a first AMI in young patients (ACE, CYP11B2 polymorphisms), but not in the disease progression after a long follow-up period. Larger collaborative studies are needed to confirm these results.
PMCID: PMC1890543  PMID: 17519002
Journal of human hypertension  2009;23(6):407-414.
Oral contraceptive (OC) use is associated with increased intra-renal renin-angiotensin-aldosterone system (RAA System) activity and risk of nephropathy, though the contribution of progestins contained in the OC in the regulation of angiotensin-dependent control of the renal circulation has not been elucidated. Eighteen OC users (8 non-diabetic, 10 Type 1 diabetic) were studied in high salt balance, a state of maximal RAA System suppression. Progestational and androgenic activity of the progestin in each OC was standardized to that of the reference progestin norethindrone. Renal plasma flow (RPF) was measured by paraaminohippurate clearance at baseline and in response to angiotensin converting enzyme (ACE)-inhibition. There was a positive correlation between OC progestational activity and the RPF response to ACE-inhibition (r=0.52, p=0.03). Similar results were noted with OC androgenic activity (r=0.54, p=0.02). On subgroup analysis, only non-diabetic subjects showed an association between progestational activity and angiotensin-dependent control of the renal circulation (r=0.71, p=0.05 non-diabetic; r=0.14, p=0.7 diabetic; p=0.07 between groups). Similar results were noted with respect to androgenic activity (r=0.88, p=0.005 non-diabetic; r=−0.33, p=0.3 diabetic; p=0.002 between groups). Our results suggest that the OC progestin component is a significant influence on the degree of angiotensin-dependent control of the renal circulation, though these findings may not apply to women with diabetes.
PMCID: PMC3712637  PMID: 19158821
Progestational activity; Androgenic activity; Renal plasma flow; Female Oral contraceptive
Epidemiological studies support the notion that arterial stiffness is an independent predictor of adverse cardiovascular events contributing significantly to systolic hypertension, impaired ventricular-arterial coupling and diastolic dysfunction, impairment in myocardial oxygen supply and demand, and progression of kidney disease. Although arterial stiffness is associated with aging, it is accelerated in the presence of obesity and diabetes. The prevalence of arterial stiffness parallels the increase of obesity that is occurring in epidemic proportions and is partly driven by a sedentary life style and consumption of a high fructose, high salt, and high fat western diet. Although the underlying mechanisms and mediators of arterial stiffness are not well understood, accumulating evidence supports the role of insulin resistance and endothelial dysfunction. The local tissue renin-angiotensin-aldosterone system (RAAS) in the vascular tissue and immune cells and perivascular adipose tissue is recognized as an important element involved in endothelial dysfunction which contributes significantly to arterial stiffness. Activation of vascular RAAS is seen in humans and animal models of obesity and diabetes, and associated with enhanced oxidative stress and inflammation in the vascular tissue. The cross talk between angiotensin and aldosterone underscores the importance of mineralocorticoid receptors in modulation of insulin resistance, decreased bioavailability of nitric oxide, endothelial dysfunction, and arterial stiffness. In addition, both innate and adaptive immunity are involved in this local tissue activation of RAAS. In this review we will attempt to present a unifying mechanism of how environmental and immunological factors are involved in this local tissue RAAS activation, and the role of this process in the development of endothelial dysfunction and arterial stiffness and targeting tissue RAAS activation.
PMCID: PMC3810594  PMID: 24194732
renin-angiotensin-aldosterone system; arterial stiffness; insulin resistance; endothelial dysfunction; obesity; diabetes

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