Systemic Renin-angiotensin System Activity Research Articles

Fasting increases circulating angiotensin levels and brain Agtr1a expression in male rats.

In addition to being recognised for involvement in cardiovascular control and hydromineral balance, the renin-angiotensin system (RAS) has also been associated with the neuroendocrine control of energy balance. One of the main brain sites for angiotensin II (ANG II)/type 1 receptor (AT1 R) signalling is the subfornical organ (SFO), a circumventricular organ related to the control of autonomic functions, motivated behaviours and energy metabolism. Thus, we hypothesised that circulating ANG II may act on the SFO AT1 R receptors to integrate metabolic and hydromineral balance. We evaluated whether food deprivation can modulate systemic RAS activity and Agrt1a brain expression, and if ANG II/AT1 R signalling influences the hypothalamic expression of mRNAs encoding neuropeptides and food and water ingestion in fed and fasted Wistar rats. We found a significant increase in both ANG I and ANG II plasma levels after 24 and 48 h of fasting. Expression of Agrt1a mRNA in the SFO and paraventricular nucleus (PVN) also increased after food deprivation for 48 h. Treatment of fasted rats with low doses of losartan in drinking water attenuated the decrease in glycemia and meal-associated water intake without changing the expression in PVN or arcuate nucleus of mRNAs encoding selected neuropeptides related to energy homeostasis control. These findings point to a possible role of peripheral ANG II/SFO-AT1 R signalling in the control of refeeding-induced thirst. On the other hand, intracerebroventricular losartan treatment decreased food and water intake over dark time in fed but not in fasted rats.

Systemic ß adrenergic stimulation/ sympathetic nerve system stimulation influences intraocular RAS through cAMP in the RPE

Several lines of evidence support the existence of a renin-angiotensin system (RAS) in the retina that is separated from the blood stream by the retinal pigment epithelium (RPE). Under physiological conditions, increased activity of intraretinal RAS regulates neuronal activity of the retina but patho-physiologically participates in retinal degeneration such as hypertensive or diabetic retinopathy. Interestingly, the RPE appears to be a modulator of intraretinal RAS in response to changes in systemic RAS. As increased systemic RAS activity is associated with increased sympathetic tonus, we investigated whether systemic β-adrenergic stimulation of the RPE also modulates renin expression in the RPE. In vivo, the mouse RPE expresses the β-adrenergic receptor subtypes 1 and 2. Staining of retina sagittal sections showed tyrosine hydroxylase positive nerve endings in the choroid indicating adrenaline/noradrenaline production sites in close proximity to the RPE. Systemic infusion of isoproterenol increased renin expression in the RPE but not in the retina. This increase was sensitive to concomitant systemic application of the angiotensin-2 receptor-type-1 blocker losartan. In vitro analysis of renin gene expression using polarized porcine RPE showed that the activity of the renin promoter can be increased by cAMP stimulation (IBMX/forskolin) but was not influenced by angiotensin-2. Thus, with the identification of the β-adrenergic system we added a new regulator of the retinal RAS with relevance for retinal function and pathology. Furthermore, it appears that the RPE is not only a close interaction partner of the photoreceptors but also a regulator or retinal activity in general.

Abstract 073: The Association Between Plasma Soluble Prorenin Receptor and Renin Activity Points Toward Renin Angiotensin System Activation and Cardiovascular Complications in Women With Type-2 Diabetes

Activation of the renin-angiotensin system (RAS) increases the risk of hypertension and chronic kidney disease (CKD) in patients with type 2 diabetes mellitus (T2DM). The prorenin receptor (PRR), a component of the RAS, activates prorenin via a non-catalytic mechanism. High levels of the soluble form of PRR (sPRR) have been reported in patients with cardiovascular (CV) diseases, including essential hypertension, CKD, preeclampsia, and gestational diabetes. Increased systemic prorenin in T2DM subjects raises the concern whether CV complications are due to augmented levels of plasma sPRR. To test the hypothesis that increased plasma sPRR is associated with systemic RAS activation, CV complications, and decline in renal function, we measured plasma sPRR, plasma renin activity (PRA), and biomarkers of renal dysfunction in 269 patients (mean age, 48 ± 1 years; 42% men, 58% women), including 173 controls (CT) and 96 patients with T2DM. Plasma sPRR levels measured by ELISA were higher in T2DM patients (19.2 ± 7.6 ng/mL) compared with CT (16.5 ± 0.4 ng/mL; p<0.001). Plasma levels of sPRR contrasted between T2DM and CT patients of same sex (Women: 20 ± 1.11 vs. 15.3 ± 0.3 ng/mL; p<0.001; Men: 17 ± 1 vs. 18 ± 0.5 ng/mL; p=0.18). PRA was augmented in T2DM patients, including Men: 9.8 ± 3,6 vs. Ang I/mL/hr; p<0.001, and even greater in Women: 13.5 ± 1.1 vs. 3.1 ± 0.3 Ang I/mL/hr; p<0.001. Increases in sPRR and PRA paralleled with hypertension, declined eGFR, and albumin/creatinine ratio in T2DM patients. Interestingly, PRA was positively correlated with plasma sPRR in women (r=0.49; p<0.001) but not in men (r=0.15 1; p=0.207). Multiple regression analysis, adjusted by age, BMI, and groups supports the association between plasma sPRR and T2DM status in women (p<0.001) but not in men. In conclusion: 1) Plasma sPRR is associated with PRA in T2DM women but not in men; and 2) The association between sPRR and PRA predisposes women with T2DM to systemic RAS activation and CV complications, as hypertension and CKD. Plasma sPRR reflects systemic RAS activation and has the potential to be a biomarker of T2DM and CV complications, particularly in women.

Effect of Uric Acid Lowering on Renin-Angiotensin-System Activation and Ambulatory BP: A Randomized Controlled Trial.

Higher serum uric acid levels, even within the reference range, are strongly associated with increased activity of the renin-angiotensin system (RAS) and risk of incident hypertension. However, the effect of lowering serum uric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting. In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adults with serum uric acid ≥5.0 mg/dl to uric acid lowering with either probenecid or allopurinol, or to placebo. The primary endpoints were kidney-specific and systemic RAS activity. Secondary endpoints included mean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping. Allopurinol and probenecid markedly lowered serum uric acid after 4 and 8 weeks compared with placebo (mean serum uric acid in allopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and 5.6 mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flow response to captopril (in ml/min per 1.73 m2) from baseline to 8 weeks, was -4 (-25 to 32) in the probenecid group (P=0.83), -4 (-16 to 9) in the allopurinol group (P=0.32), and 1 (-21 to 17) in the placebo group (P=0.96), with no significant treatment effect (P=0.77). Similarly, plasma renin activity and plasma angiotensin II levels did not significantly change with treatment. The change in mean (±SD) 24-hour systolic BPs from baseline to 8 weeks was -1.6±10.1 with probenecid (P=0.43), -0.4±6.1 with allopurinol (P=0.76), and 0.5±6.0 with placebo (P=0.65); there was no significant treatment effect (P=0.58). Adverse events occurred in 9%, 12%, and 2% of those given probenecid, allopurinol, or placebo, respectively. In contrast to animal experiments and observational studies, this randomized, placebo-controlled trial found that uric acid lowering had no effect on kidney-specific or systemic RAS activity after 8 weeks or on mean systolic BP. These data do not support the hypothesis that higher levels of uric acid are a reversible risk factor for increased BP.

Renin-Angiotensin Activation and Oxidative Stress in Early Heart Failure with Preserved Ejection Fraction.

Animal models have suggested a role of renin-angiotensin system (RAS) activation and subsequent cardiac oxidation in heart failure with preserved ejection fraction (HFpEF). Nevertheless, RAS blockade has failed to show efficacy in treatment of HFpEF. We evaluated the role of RAS activation and subsequent systemic oxidation in HFpEF. Oxidative stress markers were compared in 50 subjects with and without early HFpEF. Derivatives of reactive oxidative metabolites (DROMs), F2-isoprostanes (IsoPs), and ratios of oxidized to reduced glutathione (E h GSH) and cysteine (E h CyS) were measured. Angiotensin converting enzyme (ACE) levels and activity were measured. On univariate analysis, HFpEF was associated with male sex (p = 0.04), higher body mass index (BMI) (p = 0.003), less oxidized E h CyS (p = 0.001), lower DROMs (p = 0.02), and lower IsoP (p = 0.03). Higher BMI (OR: 1.3; 95% CI: 1.1–1.6) and less oxidized E h CyS (OR: 1.2; 95% CI: 1.1–1.4) maintained associations with HFpEF on multivariate analysis. Though ACE levels were higher in early HFpEF (OR: 1.09; 95% CI: 1.01–1.05), ACE activity was similar to that in controls. HFpEF is not associated with significant systemic RAS activation or oxidative stress. This may explain the failure of RAS inhibitors to alter outcomes in HFpEF.

Effect of acute and chronic vitamin D administration on systemic renin angiotensin system in essential hypertensives and controls

To investigate the systemic renin-angiotensin system (RAS) in essential hypertensives (EH) and controls (C) after short- and long-term vitamin D receptor activation. Ten consecutive EH (under controlled low-salt diet) and 10 C underwent calcitriol administration (0.25 μg bid) for 1 week (Group A). Eighteen consecutive EH under angiotensin II receptor antagonist therapy received a single oral dose of 300,000 IU of cholecalciferol and were followed up for 8 weeks (Group B). In basal conditions and at the end of the study (1 week in Group A and 8 weeks in Group B), plasma renin activity (PRA), plasma active renin, aldosterone, and angiotensin II were evaluated, as well as blood pressure, plasma 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and PTH. In Group A, plasma 25(OH)D levels in EH and C were below the normal range, although lower levels were found in the former. No association between basal plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS components was observed either in the whole group or in the two subgroups. Calcitriol administration did not affect any RAS parameter either in EH or in C. In Group B, cholecalciferol significantly increased 25(OH)D and 1,25(OH)2D levels without interfering with the angiotensin II receptor antagonist-induced increase in RAS components. No correlation was found between plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS parameters before and after cholecalciferol administration. The present data suggest that, in our experimental conditions, vitamin D receptor activation is unable to influence systemic RAS activity.

Cholecalciferol administration blunts the systemic renin–angiotensin system in essential hypertensives with hypovitaminosis D

Vitamin D plasma levels are negatively associated with blood pressure and cardiovascular mortality, and vitamin D supplementation reduces cardiovascular events. Renin-angiotensin system (RAS) suppression may be one of the mechanisms involved. However, there are no interventional prospective studies demonstrating a reduction in circulating RAS components after vitamin D treatment. Fifteen consecutive drug-free patients with essential hypertension and hypovitaminosis D underwent therapy with an oral dose of 25000 I.U. of cholecalciferol once a week for two months, while maintaining a constant-salt diet. In basal conditions and at the end of the study, RAS activity (plasma angiotensinogen, renin, PRA, angiotensin II, aldosterone and urinary angiotensinogen) was investigated, in addition to blood pressure and plasma vitamin D levels (25(OH)D). After cholecalciferol administration, all patients exhibited normalized plasma 25(OH)D values. At the end of the study, a reduction (p < 0.05) in plasma renin and aldosterone, and a decrement, although not significant, of PRA and angiotensin II, was observed. No difference was found in plasma and urinary angiotensinogen or blood pressure values. Our data indicate that in essential hypertensives with hypovitaminosis D, pharmacological correction of vitamin D levels can blunt systemic RAS activity.

Activation of systemic, but not local, renin-angiotensin system is associated with up-regulation of TNF-α during prolonged fasting in northern elephant seal pups

Northern elephant seal pups naturally endure a 2-3 month post-weaning fast that is associated with activation of systemic renin-angiotensin system (RAS), a decrease in plasma adiponectin (Acrp30), and insulin resistance (IR)-like conditions. Angiotensin II (Ang II) and tumor necrosis factor-alpha (TNF-α) are potential causal factors of IR, while Acrp30 may improve insulin signaling. However, the effects of fasting-induced activation of RAS on IR-like conditions in seals are not well described. To assess the effects of prolonged food deprivation on systemic and local RAS, and their potential contribution to TNF-α as they relate to an IR condition, the mRNA expressions of adipose and muscle RAS components and immuno-relevant molecules were measured along with plasma RAS components. Mean plasma renin activity and Ang II concentrations increased by 89 and 1658%, respectively, while plasma angiotensinogen (AGT) decreased by 49% over the fast, indicative of systemic RAS activation. Prolonged fasting was associated with decreases in adipose and muscle AGT mRNA expressions of 69 and 68%, respectively, corresponding with decreases in tissue protein content, suggesting suppression of local AGT production. Muscle TNF-α mRNA and protein increased by 239 and 314%, whereas those of adipose Acrp30 decreased by 32 and 98%, respectively. Collectively, this study suggests that prolonged fasting activates a systemic RAS, which contributes to an increase in muscle TNF-α and suppression of adipose Acrp30. This targeted and tissue-specific regulation of TNF-α and Acrp30 is likely coordinated to synergistically contribute to the development of an IR-like condition, independent of local RAS activity. These data enhance our understanding of the adaptive mechanisms evolved by elephant seals to tolerate potentially detrimental conditions.

Role of H2O2 in hypertension, renin‐angiotensin system activation and renal medullary disfunction caused by angiotensin II

Activation of the intrarenal renin-angiotensin system (RAS) and increased renal medullary hydrogen peroxide (H(2) O(2) ) contribute to hypertension. We examined whether H(2) O(2) mediated hypertension and intrarenal RAS activation induced by angiotensin II (Ang II). Ang II (200 ng·kg(-1) ·min(-1) ) or saline were infused in Sprague Dawley rats from day 0 to day 14. Polyethylene glycol (PEG)-catalase (10 000 U·kg(-1) ·day(-1) ) was given to Ang II-treated rats, from day 7 to day 14. Systolic blood pressure was measured throughout the study. H(2) O(2) , angiotensin AT(1) receptor and Nox4 expression and nuclear factor-κB (NF-κB) activation were evaluated in the kidney. Plasma and urinary H(2) O(2) and angiotensinogen were also measured. Ang II increased H(2) O(2) , AT(1) receptor and Nox4 expression and NF-κB activation in the renal medulla, but not in the cortex. Ang II raised plasma and urinary H(2) O(2) levels, increased urinary angiotensinogen but reduced plasma angiotensinogen. PEG-catalase had a short-term antihypertensive effect and transiently suppressed urinary angiotensinogen. PEG-catalase decreased renal medullary expression of AT(1) receptors and Nox4 in Ang II-infused rats. Renal medullary NF-κB activation was correlated with local H(2) O(2) levels and urinary angiotensinogen excretion. Loss of antihypertensive efficacy was associated with an eightfold increase of plasma angiotensinogen. The renal medulla is a major target for Ang II-induced redox dysfunction. H(2) O(2) appears to be the key mediator enhancing intrarenal RAS activation and decreasing systemic RAS activity. The specific control of renal medullary H(2) O(2) levels may provide future grounds for the treatment of hypertension.

Losartan prevents body weight gain in diet induced obese rats

The renin angiotensin system (RAS), best known for its involvement in the regulation of cardiovascular function and salt/water balance, has recently been suggested to play a role in the regulation of energy homeostasis as interference with systemic RAS activity has been shown to decrease body weight and fat. The present study was undertaken to determine whether losartan, a non‐peptide ATII Type 1 receptor blocker, would influence daily body weight gain in diet induced obese (DIO) rats.Male Sprague Dawley rats (125–150g) were exposed to either a HFD or fed standard rat chow. After 10 weeks, rats on HFD were divided into DIO or diet resistant (DR) and at 18 weeks, body weight, and food and water intake were measured daily for 5 weeks. After a 14 day control period, rats were administered losartan (30mg/kg) in drinking water for 14 days, followed by return to tap water for an additional 7 days and effects on body weight and food and water intake assessed.There was no difference in daily body weight gain during in the control period between chow fed (2.6±0.5g, n=8), DR (2.1±0.5g, n=8) or DIO rats (3.4±0.4g, n=8, p=.18, one way ANOVA). Although losartan treatment attenuated daily body weight gain in chow fed rats (1.25±0.5g, n=8), it completely abolished daily weight gain in DR (−0.65±0.3g, n=8) and DIO (−0.43±0.7g, n=8) rats. Upon return to normal tap water, all rats gained weight as they had prior to losartan administration (chow 3.3±0.2g, DR 2.9±0.5g, DIO 3.8±0.5g).Our data demonstrate that losartan attenuates body weight gain in rats fed either a HFD (DR and DIO) or chow diet, an effect which was more pronounced in animals fed the HFD. These data suggest that the RAS plays a role in body weight homeostasis and that pharmacological agents that interfere with the functioning of the RAS may have be useful in the treatment for obesity.

The renin-angiotensin system and hypertension in autosomal recessive polycystic kidney disease

Hypertension is a well-recognized complication of autosomal recessive polycystic kidney disease (ARPKD). The renin-angiotensin system (RAS) is a key regulator of blood pressure; however, data on the RAS in ARPKD are limited and conflicting, showing both up- and down-regulation. In the current study, we characterized intrarenal and systemic RAS activation in relationship to hypertension and progressive cystic kidney disease in the ARPKD orthologous polycystic kidney (PCK) rat. Clinical and histological measures of kidney disease, kidney RAS gene expression by quantitative real-time PCR, angiotensin II (Ang II) immunohistochemistry, and systemic Ang I and II levels were assessed in 2-, 4-, and 6-month-old cystic PCK and age-matched normal rats. PCK rats developed hypertension and progressive cystic kidney disease without significant worsening of renal function or relative kidney size. Intrarenal renin, ACE and Ang II expression was increased significantly in cystic kidneys; angiotensinogen and Ang II Type I receptor were unchanged. Systemic Ang I and II levels did not differ. This study demonstrates that intrarenal, but not systemic, RAS activation is a prominent feature of ARPKD. These findings help reconcile previous conflicting reports and suggest that intrarenal renin and ACE gene upregulation may represent a novel mechanism for hypertension development or exacerbation in ARPKD.

Relationship between Insulin Resistance and the Renin-Angiotensin System: Analysis for Patients with Essential and Renovascular Hypertension

Insulin resistance is frequently observed in patients with essential hypertension (EHT), and the renin-angiotensin system (RAS) has been demonstrated to modulate the status of insulin resistance. The aims of present study are to investigate the relationship between systemic RAS and insulin resistance in 82 patients with EHT and compare the impact of RAS to insulin resistance with 10 renovascular hypertension (RVHT) patients who have a highly activated systemic RAS. From patients who were admitted to our hospital, patients with overt diabetes and hypertensives who had secondary HT except RVHT or chronic renal failure were excluded. Plasma renin activity (PRA) was used as an indicator of systemic RAS activity. HOMA-R as an index of insulin resistance and sum of immunoreactive insulin (IRI) during glucose tolerance test (∑IRI) and IRI at 120 minutes (IRI120) were used as indices of hyperinsulinemia. In the EHT patients, circulating PRA showed an independent relationship with IRI120 and ∑IRI after adjusting confounding factors (IRI120: t = 2.70, p = 0.01, ∑IRI: t = 3.05, p < 0.001). Excluding patients who were taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blocker (ARBs), the relationship remained in univariate linear regression; after adjustment for confounding factors, PRA showed a tendency to be correlated with ∑IRI. However, there was no significant relationship between PRA and indices of insulin resistance and hyperinsulinemia in patients with RVHT. In conclusion, the systemic RAS may modulate insulin sensitivity in EHT patients.

Current concepts of renal hemodynamics in diabetes

Glomerular hyperfiltration has long been recognized in insulin-dependent diabetes, and has been more recently recognized in patients with non-insulin dependent diabetes mellitus as well. Experimentally, glomerular hyperfiltration has been shown to result from elevations in the glomerular capillary blood flow and the glomerular capillary hydraulic pressure (P GC). Of the hemodynamic determinants of hyperfiltration, it is glomerular hypertension that is most damaging to the glomerulus. Experimental and clinical studies have confirmed that antihypertensive agents that lower P GC more consistently slow the progression of injury than do those that fail to control glomerular hypertension. The pathogenesis of diabetic hyperfiltration is multifactoral. Many mediators have been proposed, including changes due to the altered metabolic milieu, and alterations in endogenous levels of such vasoactive mediators as atrial natriuretic peptide, endothelial-derived relaxing factor, angiotensin II, prostaglandins, thromboxanes, and kinins, among others. It has more recently been suggested that local renal tissue levels, rather than circulating levels, play the more profound role in hemodynamic regulation. For example, the renin-angiotensin system (RAS) appears to be disproportionately active in the renal tissue, potentially explaining the renal vascular responsiveness to angiotensin-converting enzyme inhibition despite absence of systemic RAS activation. Little is yet known of the mechanisms by which glomerular hypertension leads to injury. Innovative new in vitro systems have been developed to address this question. These studies postulate that glomerular hemodynamic factors (shear stress, pulsatile flow) modify the growth and activity of glomerular component cells, inducing the expression of cytokines and other mediators, which then stimulate matrix production and promote structural injury.