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Background: The renin-angiotensin-aldosterone system (RAAS) is an important driver of blood pressure (BP), but the association of the RAAS with ambulatory BP (ABP) and ABP monitoring phenotypes among African Americans has not been assessed., Methods: ABP and ABP monitoring phenotypes were assessed in 912 Jackson Heart Study participants with aldosterone and plasma renin activity (PRA). Multivariable linear and logistic regression analyses were used to analyze the association of aldosterone and PRA with clinic, awake, and asleep systolic BP and diastolic BP (DBP) and ABP monitoring phenotypes, adjusting for important confounders., Results: The mean age of participants was 59±11 years and 69% were female. In fully adjusted models, lower log-PRA was associated with higher clinic, awake, and asleep systolic BP and DBP (all P <0.05). A higher log-aldosterone was associated with higher clinic, awake, and asleep DBP (all P <0.05). A 1-unit higher log-PRA was associated with lower odds of daytime hypertension (odds ratio [OR] 0.59 [95% CI, 0.49-0.71]), nocturnal hypertension (OR, 0.68 [95% CI, 0.58-0.79]), daytime and nocturnal hypertension (OR, 0.59 [95% CI, 0.48-0.71]), sustained hypertension (OR, 0.52 [95% CI, 0.39-0.70]), and masked hypertension (OR 0.75 [95% CI, 0.62-0.90]). A 1-unit higher log-aldosterone was associated with higher odds of nocturnal hypertension (OR, 1.38 [95% CI, 1.05-1.81]). Neither PRA nor aldosterone was associated with percent dipping, nondipping BP pattern, or white-coat hypertension. Patterns for aldosterone:renin ratio were similar to patterns for PRA., Conclusions: Suppressed renin activity and higher aldosterone:renin ratios were associated with higher systolic BP and DBP in the office and during the awake and asleep periods as evidenced by ABP monitoring. Higher aldosterone levels were associated with higher DBP, but not systolic BP, in the clinic and during the awake and asleep periods. Further clinical investigation of novel and approved medications that target low renin physiology such as epithelial sodium channel inhibitors and mineralocorticoid receptor antagonists may be paramount in improving hypertension control in African Americans.

Several cardiac and renal diseases are attributed to a dysregulation of the renin-angiotensin system. Renin, the rate-limiting enzyme of the renin-angiotensin system, has 2 isoforms. The classical renin isoform (renin-a) encoding preprorenin is mainly confined to the juxtaglomerular cells and released into the circulation upon stimulation. Alternatively, renin-b is predicted to remain intracellular and is expressed in the brain, heart, and adrenal gland. In the brain, ablation of renin-b (Ren-b Null mice) results in increased brain renin-angiotensin system activity. However, the consequences of renin-b ablation in tissues outside the brain remain unknown. Therefore, we hypothesized that renin-b protects from hypertensive cardiac and renal end-organ damage in mice. Ren-b Null mice exhibited normal blood pressure at baseline. Thus, we induced hypertension by using a slow pressor dose of Ang II (angiotensin II). Ang II increased blood pressure in both wild type and Ren-b Null to the same degree. Although the blood pressure between Ren-b Null and wild-type mice was elevated equally, 4-week infusion of Ang II resulted in exacerbated cardiac remodeling in Ren-b Null mice compared with wild type. Ren-b Null mice also exhibited a modest increase in renal glomerular matrix deposition, elevated plasma aldosterone, and a modestly enhanced dipsogenic response to Ang II. Interestingly, ablation of renin-b strongly suppressed plasma renin, but renal cortical renin mRNA was preserved. Altogether, these data indicate that renin-b might play a protective role in the heart, and thus renin-b could be a potential target to treat hypertensive heart disease.

Background: To investigate the relationships of plasma renin, angiotensin, and aldosterone levels to blood pressure variability and target organ damage in children with essential hypertension., Methods: A case-control study was conducted on 132 children diagnosed with essential hypertension (103 males and 29 females with the mean age of 11.8 ± 2.4 years). The plasma RAAS levels were measured using the enhanced chemiluminescence method, the ambulatory blood pressure was monitored for 24 h, and then the average real variability (ARV) was calculated. Data on indicators were used for assessing cardiac and renal damages. The correlations of plasma renin, angiotensin, and aldosterone (RAAS) levels to blood pressure variability (BPV) and target organ damage (TOD) were studied. A comparison between the groups was conducted using SPSS 20., Results: Among the 132 children, 55 cases had target organ damage. The 24-h ARV and the daytime ARV of the systolic blood pressure of the high angiotensin II (AT II) group was significantly higher than that of the normal AT II group (t = 2.175, P = 0.031; t = 2.672, P = 0.009). Plasma AT II and aldosterone levels were significantly associated with the left ventricular mass index (r = 0.329, P = 0.0001; r = 0.175, P = 0.045). Linear regression analysis showed that AT II [β ± s.e. = 0.025 ± 0.006, 95% CI (0.013-0.038), P = 0.0001] and aldosterone [β ± s.e. = 0.021 ± 0.007, 95% CI (0.008-0.034), P = 0.002] were risk factors for LVH., Conclusions: The AT II level in children with essential hypertension affected the variability of the 24-h and the daytime SBP. Plasma AT II and aldosterone levels were associated with cardiac damage. Results from this study indicated that AT II and aldosterone are risk factors for LVH in childhood hypertension and are of great significance for improving the clinical prognosis of pediatric patients with hypertension.

Accumulating evidence supports that the brain renin-angiotensin system (RAS), including prorenin (PR) and its receptor (PRR), two newly discovered RAS players, contribute to sympathoexcitation in salt-sensitive hypertension. Still, whether PR also contributed to elevated circulating levels of neurohormones such as vasopressin (VP) during salt-sensitive hypertension, and if so, what are the precise underlying mechanisms, remains to be determined. To address these questions, we obtained patch-clamp recordings from hypothalamic magnocellular neurosecretory neurons (MNNs) that synthesize the neurohormones oxytocin and VP in acute hypothalamic slices obtained from sham and deoxycorticosterone acetate (DOCA)-salt-treated hypertensive rats. We found that focal application of PR markedly increased membrane excitability and firing responses in MNNs of DOCA-salt, compared with sham rats. This effect included a shorter latency to spike initiation and increased numbers of spikes in response to depolarizing stimuli and was mediated by a more robust inhibition of A-type K + channels in DOCA-salt compared with sham rats. On the other hand, the afterhyperpolarizing potential mediated by the activation of Ca 2+ -dependent K + channel was not affected by PR. mRNA expression of PRR, VP, and the Kv4.3 K + channel subunit in the supraoptic nucleus of DOCA-salt hypertensive rats was increased compared with sham rats. Finally, we report a significant decrease of plasma VP levels in neuron-selective PRR knockdown mice treated with DOCA-salt, compared with wild-type DOCA-salt-treated mice. Together, these results support that activation of PRR contributes to increased excitability and firing discharge of MNNs and increased plasma levels of VP in DOCA-salt hypertension. NEW & NOTEWORTHY Our studies support that prorenin (PR) and its receptor (PRR) within the hypothalamus contribute to elevated plasma vasopressin levels in deoxycorticosterone acetate-salt hypertension, in part because of an exacerbated effect of PR on magnocellular neurosecretory neuron excitability; Moreover, our study implicates A-type K+ channels as key underlying molecular targets mediating these effects. Thus, PR/PRR stands as a novel therapeutic target for the treatment of neurohumoral activation in salt-sensitive hypertension.

Introduction: Hypertension, particularly in black populations, is often accompanied by augmented sympathetic nervous system activity and suppressed renin activity, indicative of possible blood pressure (BP) dysregulation. The potential role of the interrelationship between the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system in the context of low-renin conditions is unclear. We therefore explored whether surrogate measures of sympathetic activity [noradrenaline, 24-hour heart rate (HR) and percentage (%) dipping of night-time HR] relate to renin, aldosterone and aldosterone-to-renin ratio (ARR) in black and white South Africans., Methods: We included black (n = 127) and white (n = 179) males and females aged 20-63 years. We measured 24-hour BP and HR, and calculated night-time dipping. We determined renin and aldosterone levels in plasma and calculated ARR. Noradrenaline and creatinine levels were determined in urine and the noradrenaline:creatinine ratio was calculated., Results: More blacks had low renin levels (80.3%) compared to whites (58.7%) (p < 0.001). In univariate and after multivariate analyses the following significant associations were evident in only the black group: HR dipping was associated negatively with aldosterone level (β = -0.18, p = 0.024) and ARR (β = -0.20, p = 0.011), while 24-hour HR was associated positively with renin level (β = 0.20, p = 0.024). Additionally, there was a borderline significant positive association between noradrenaline:creatinine ratio and aldosterone level (β = 0.19, p = 0.051)., Conclusions: The observed associations between surrogate measures of sympathetic nervous system activity and components of the RAAS in the black group suggest that the adverse effects of aldosterone and its ratio to renin on the cardiovascular system may be coupled to the effects of the sympathetic nervous system.

Using a transgenic cross, we evaluated features of preeclampsia, renal injury and the sFlt1/VEGF changes. Transgenic hAGT and hREN, or wild-type (WT) C57Bl/6 mice were cross-bred: female hAGT × male hREN for preeclampsia (PRE) model and female WT × male WT for pregnant controls (WTP). Samples were collected for plasma VEGF, sFlt1, and urine albumin. Blood pressures (BP) were monitored by telemetry. Vascular reactivity was investigated by wire myography. Kidneys and placenta were immunostained for sFlt1 and VEGF. Eleven PRE and 9 WTP mice were compared. PRE more frequently demonstrated albuminuria, glomerular endotheliosis (80% vs. 11%; P = 0.02), and placental necrosis (60% vs. 0%; P < 0.01). PRE group demonstrated declining BPs with advancing gestation. Plasma sFlt1 increased across pregnancy in PRE; VEGF did not vary. IHC demonstrated the presence of sFlt1 in glomeruli, lymphatics, and collecting tubules of PRE kidneys, suggesting excretion. VEGF immunostaining was increased specifically in the glomeruli of PRE kidneys. Placenta in PRE showed marked immunostaining for sFlt1. We conclude that this transgenic model of preeclampsia recapitulates human preeclamptic state with high fidelity, and that, vascular adaptation to pregnancy is suggested by declining BPs and reduced vascular response to PE and increased response to acetylcholine. Placental damage with resultant increased release of sFlt1, proteinuria, deficient spiral artery remodeling, and glomerular endotheliosis were observed in this model of PRE. Increased VEGF binding to glomerular endothelial cells in this model of PRE is similar to human PRE and leads us to hypothesize that renal injury in preeclampsia may be mediated through local VEGF., (Copyright © 2017 the American Physiological Society.)

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as antihypertensive therapy for patients with resistant hypertension. However, the influence of variations in salt intake on blood pressure lowering during baroreflex activation (BA) has not yet been determined. As the sensitivity of arterial pressure to salt intake is linked to the responsiveness of renin secretion, we determined steady-state levels of arterial pressure and neurohormonal responses in 6 dogs on low, normal, and high salt intakes (5, 40, 450 mmol/d, respectively) under control conditions and during a 7-day constant level of BA. Under control conditions, there was no difference in mean arterial pressure at low (92±1) and normal (92±2 mm Hg) sodium intakes, but pressure increased 9±2 mm Hg during high salt. Plasma renin activity (2.01±0.23, 0.93±0.20, 0.01±0.01 ng angiotensin I/mL/h) and plasma aldosterone (10.3±1.9, 3.5±0.5, 1.7±0.1 ng/dL) were inversely related to salt intake, whereas there were no changes in plasma norepinephrine. Although mean arterial pressure (19-22 mm Hg) and norepinephrine (20%-40%) were lower at all salt intakes during BA, neither the changes in pressure nor the absolute values for plasma renin activity or aldosterone in response to salt were different from control conditions. These findings demonstrate that suppression of sympathetic activity by BA lowers arterial pressure without increasing renin release and indicate that changes in sympathetic activity are not primary mediators of the effect of salt on renin secretion. Consequently, blood pressure lowering during BA is independent of salt intake., (© 2014 American Heart Association, Inc.)

Studies in experimental animals and younger women suggest a protective role for estrogen; however, clinical trials may not substantiate this effect in older females. Therefore, the present study assessed the outcome of ovariectomy in older mRen2. Lewis rats subjected to a high-salt diet for 4 wk. Intact or ovariectomized (OVX, 15 wk of age) mRen2. Lewis rats were aged to 60 wk and then placed on a high-salt (HS, 8% sodium chloride) diet for 4 wk. Systolic blood pressures were similar between groups [OVX 169 +/- 6 vs. Intact 182 +/- 7 mmHg; P = 0.22] after the 4-wk diet; however, proteinuria [OVX 0.8 +/- 0.2 vs. Intact 11.5 +/- 2.6 mg/mg creatinine; P < 0.002, n = 6], renal interstitial fibrosis, glomerular sclerosis, and tubular casts were lower in OVX vs. Intact rats. Kidney injury molecule-1 mRNA, a marker of tubular damage, was 53% lower in the OVX HS group. Independent from blood pressure, OVX HS rats exhibited significantly lower cardiac (24%) and renal (32%) hypertrophy as well as lower C-reactive protein (28%). Circulating insulin-like growth factor-I (IGF-I) levels were not different between the Intact and OVX groups; however, renal cortical IGF-I mRNA and protein were attenuated in OVX rats [P < 0.05, n = 6]. We conclude that ovariectomy in the older female mRen2. Lewis rat conveys protection against salt-dependent increase in renal injury.

Recently, a receptor for renin was described that may be important for vascular uptake and activation of (pro)renin, thus leading to local generation of angiotensin II. To assess the in vivo relevance of this protein, we generated transgenic rats overexpressing the human renin receptor gene in smooth muscle tissue, under the control of a 16-kb fragment of the mouse smooth muscle myosin heavy chain gene [TGR(SMMHC-HRR)]. Four lines of transgenic animals were obtained. The correct pattern of expression of the transgene was confirmed by RNase protection assay and in situ hybridization. TGR(SMMHC-HRR) rats are fertile and develop normally. After 6 months of age, transgenic rats develop a cardiovascular phenotype with an elevated systolic blood pressure (137.8+/-5 versus 118.9+/-3.7 mm Hg; P=0.008), and an augmentation in heart rate (349.1+/-7.7 versus 303.1+/-16.16 bpm; P=0.023) in TGR(SMMHC-HRR) and controls, respectively. These alterations are progressively increasing with aging. Although kidney function and plasma renin were normal in TGR(SMMHC-HRR), an increase in plasma aldosterone [TGR(SMMHC-HRR) 428+/-64.9 versus 207.3+/-73.24 pg/mL in control; P=0.02] and in aldosterone/renin ratio [TGR(SMMHC-HRR) 8.04+/-2.2 versus 2.8+/-0.55 in control; P=0.03] was observed. This suggests that renin receptor overexpression has resulted in increased intraadrenal angiotensin II, thereby provoking enhanced aldosterone generation in the absence of changes in plasma renin. The rise in aldosterone may underlie, at least in part, the observed cardiovascular phenotype of TGR(SMMHC-HRR).

Background: The renin-angiotensin and vasopressin systems, in addition to the sympathetic system, are important backup mechanisms for maintaining arterial blood pressure during circulatory challenges. We tested the hypothesis that preganglionic sympathetic blockade by thoracic epidural anesthesia interferes with the functional integrity of the renin-angiotensin system., Methods: Renin concentrations were assessed in awake non-sedated patients in response to induced arterial hypotension both before and during sympathetic blockade by thoracic epidural anesthesia (n = 10). Heart rate (electrocardiogram) and mean arterial blood pressure (electromanometry) were recorded continuously. Active renin (radioimmunoassay), vasopressin (radioimmunoassay), and osmolality (osmometry) in arterial blood were measured intermittently: (1) at baseline, (2) during a hypotensive challenge (15 min) induced by sodium nitroprusside (titrated to decrease mean arterial blood pressure by at least 25%) with the sympathetic system intact, (3) during recovery, (4) with epidural anesthesia alone (sensory blockade T1-T11), and (5) during a second hypotensive challenge and sympathetic blockade with sodium nitroprusside titrated to the same mean arterial blood pressure as with the sympathetic system intact., Results: With the sympathetic system intact hypotension almost doubled renin concentration (34 +/- 32 SD to 60 +/- 58 pg.ml-1, P = 0.019), while vasopressin concentration remained unchanged. In contrast, during sympathetic blockade and despite identical hypotension (mean arterial blood pressure 68 +/- 8 vs. 67 +/- 5 mmHg), renin concentration did not change (35 +/- 27 vs. 35 +/- 29 pg.ml-1, P = 0.5), whereas vasopressin concentration increased (4.6 +/- 2.5 to 13.4 +/- 9.4 pg.ml-1, P = 0.01). Osmolality remained unchanged., Conclusion: Our results indicate a key role of renal sympathetic fibers in mediating renin release during hypotension in humans, and that epidural anesthesia interferes with the functional integrity of the renin-angiotensin system.

We have studied the contribution of circulating renin of renal origin to renin-like activity within the arterial wall and to blood pressure. Bolus injections of renin sufficient to elevate blood pressure by 44.7 mm Hg caused aortic renin to rise from 0.13 to 1.48 ng angiotensin I/100 mg/hr in nephrectomized rats. Elevation of aortic renin was still present at 6 hours, and this was associated with significant blood pressure elevation (p less than 0.05) which could be reversed by infusion of sarcosine, alanine, angiotensin II (saralasin). Prevention of the pressor effect by pretreatment with the converting enzyme inhibitor captopril did not reduce renin uptake. When kidneys were left in situ, although significant uptake of renin could be demonstrated 1 hour after injection, the increase at 3 hours was no longer significant (p greater than 0.05) and blood pressure returned to normal by 1 1/2 hours. This change in blood pressure may be related to the much more rapid clearance of circulating renin in the presence of normal kidneys or to other renal factors influencing the blood pressure response. The present studies demonstrate therefore that most of the renin-like activity within the aortic wall is derived from plasma renin and it seems probable that this component of the renin-angiotensin system plays an important role in blood pressure maintenance in the nephrectomized rats injected with renin. The relationship is less obvious in the presence of normal kidneys where additional influences may come into play.

BackgroundThe effects of the renin-angiotensin-aldosterone system in cardiovascular system have been described based on small studies. The aim of this study was to evaluate the relationship between aldosterone and plasma renin activity (PRA) and cardiovascular structure and function.MethodsWe studied a random sample of Multi-Ethnic Study of Atherosclerosis participants who had aldosterone and PRA blood assays at 2003-2005 and underwent cardiac magnetic resonance at 2010. Participants taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were excluded.ResultsThe aldosterone group was composed by 615 participants, mean age 61.6 ± 8.9 years, while the renin group was 580 participants, mean age 61.5 ± 8.8 years and both groups had roughly 50% females. In multivariable analysis, 1 SD increment of log-transformed aldosterone level was associated with 0.07 g/m2 higher left ventricle (LV) mass index (P = 0.04) and 0.11 ml/m2 higher left atrium (LA) minimal volume index (P < 0.01). Additionally, higher log-transformed aldosterone was associated with lower LA maximum strain and LA emptying fraction (P < 0.01). Aldosterone levels were not significantly associated with aortic measures. Log-transformed PRA was associated with lower LV end diastolic volume index (β standardized = 0.08, P = 0.05). PRA levels were not significantly associated with LA and aortic structural or functional differences.ConclusionsHigher levels of aldosterone and PRA are associated with concentric LV remodeling changes. Moreover, aldosterone was related to deleterious LA remodeling changes.

Introduction: High-fructose diet (HFr) causes metabolic syndrome, and HFr-induced hypertension and renal damage are exaggerated in Dahl salt-sensitive (DS) rats. Exercise training (Ex) has antihypertensive and renal protective effects in rats fed HFr; however, there has been little discussion about the DS rats, which exhibit metabolic disturbances. This study thus examined the effects of Ex on DS rats fed HFr. Methods: Male DS rats were divided into three groups. The control group was fed a control diet, and both the HFr group and the HFr–Ex group were fed an HFr (60% fructose). The HFr–Ex group also underwent treadmill running (20 m·min−1, 60 min·d−1, 5 d·wk−1). After 12 wk, renal function, histology, and renin–angiotensin system were examined. Results: HFr increased blood pressure, urinary albumin, and creatinine clearance, and Ex inhibited these increases. HFr induced glomerular sclerosis, podocyte injury, afferent arteriole thickening, and renal interstitial fibrosis, and Ex ameliorated them. HFr reduced plasma renin activity, and Ex further reduced the activity. HFr also increased the expression of angiotensinogen, renin, angiotensin-converting enzyme (ACE), and angiotensin II type 1 receptor, and Ex restored the ACE expression to the control levels. HFr decreased the expression of ACE2, angiotensin II type 2 receptor, and Mas receptor, and Ex restored the ACE2 and Mas receptor expressions to the control levels and further decreased the angiotensin II type 2 receptor expression. HFr increased the ACE activity and decreased the ACE2 activity, and Ex restored these activities to the control levels. Conclusions: Ex prevents HFr-induced hypertension and renal damages in DS rats. The changes in renal renin–angiotensin system may be involved in the mechanism of the antihypertensive and renal protective effects of Ex. [ABSTRACT FROM AUTHOR]

Obesity, along with type 2 diabetes mellitus (T2DM), is a major contributor to hypertension. The renin-angiotensin-aldosterone system is involved in the occurrence of diabetes and hypertension. However, the mechanism by which obesity is related to T2DM induced hypertension is unclear. In this study, we observed that blood pressure and serum renin content were increased in patients with diabetes and hypertension. Hydrogen sulfide (H2S), as an endogenous bioactive molecule, has been shown to be a vasodilator. Db/db mice, characterized by obesity and T2DM, and juxtaglomerular (JG) cells, which line the afferent arterioles at the entrance of the glomeruli to produce renin, treated with glucose, palmitic acid (PA) and oleic acid (OA), were used as animal and cellular models. NaHS, the H2S donor, was administered to db/db mice through intraperitoneal injection. NaHS significantly alleviated blood pressure in db/db mice, decreased the renin content in the serum of db/db mice and reduced renin secretion from JG cells. NaHS modulated renin release via cAMP and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), including synaptosome-associated protein 23 (SNAP23) and vesicle-associated membrane protein 2 (VAMP2), which mediate renin exocytosis. Furthermore, NaHS increased the levels of autophagy-related proteins and colocalization with EGFP-LC3 puncta with renin-containing granules and VAMP2 to consume excessive renin to maintain intracellular homeostasis. Therefore, exogenous H2S attenuates renin release and promotes renin-vesicular autophagy to relieve diabetes-induced hypertension. [ABSTRACT FROM AUTHOR]

BackgroundHigher fibroblast growth factor-23 (FGF23) concentrations have been found to be associated with incident heart failure (HF). Experimental data suggest FGF23 directly stimulates myocardial hypertrophy. FGF23 may also enhance renin-angiotensin-aldosterone system activity. Whether FGF23 is associated with increased HF risk in populations with hypertension and whether this association is weaker in the presence of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy is unknown.MethodsWe studied 2,858 adults with hypertension free of cardiovascular disease at baseline (65.6 ± 9.5 years, 46.2% male) participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We investigated the association of baseline serum intact FGF23 with incident HF over a 14-year median follow-up and whether ACEI/ARB therapy modified this risk. We also investigated the relationship of FGF23 with aldosterone and plasma renin activity in a random subgroup of the entire MESA cohort with available assays (N = 1,642).ResultsIn adjusted Cox regression models, higher FGF23 was associated with a 63% greater hazard of incident HF (hazard ratio: 1.63, 95% confidence interval: [1.13-2.36] per 1-unit increase in log-transformed FGF23), which persisted after exclusion of participants with chronic kidney disease (hazard ratio: 1.94 [1.10-3.43]). There was no heterogeneity by ACEI/ARB use (Pinteraction = 0.438). FGF23 improved model fit over covariables (likelihood ratio χ2 = 6.67, P = 0.010). In multivariable linear regression models, there was no association between FGF23 and aldosterone or plasma renin activity.ConclusionsHigher FGF23 concentrations are associated with a significantly increased risk of HF in hypertension but this risk did not differ by ACEI/ARB treatment status. FGF23 may be a useful biomarker for HF risk in hypertensive populations.

Background: The synthesis and secretion of renin in juxtaglomerular (JG) cells are closely regulated by the blood pressure. To date, however, the molecular identity through which JG cells respond to the blood pressure remains unclear. Results: Here we discovered that Piezo1, a mechanosensitive ion channel, was colocalized with renin in mouse kidney as well as As4.1 cells, a commonly used JG cell line. Activation of Piezo1 by its agonist Yoda1 induced an intracellular calcium increase and downregulated the expression of renin in these cells, while knockout of Piezo1 in JG cells abolished the effect of Yoda1. Meanwhile, mechanical stress using microfluidics also induced an intracellular calcium increase in wildtype but not Piezo1 knockout JG cells. Mechanistically, we demonstrated that activation of Piezo1 upregulated the Ptgs2 expression via the calcineurin-NFAT pathway and increased the production of Ptgs2 downstream molecule PGE2 in JG cells. Surprisingly, we discovered that increased PGE2 could decreased the renin expression through the PGE2 receptor EP1 and EP3, which inhibited the cAMP production in JG cells. In mice, we found that activation of Piezo1 significantly downregulated the renin expression and blood pressure in wildtype but not adeno-associated virus (AAV)-mediated kidney specific Piezo1 knockdown mice. Conclusions: In summary, these results revealed that activation of Piezo1 could downregulate the renin expression in JG cells and mice, subsequently a reduction of blood pressure, highlighting its therapeutic potential as a drug target of the renin-angiotensin system. [ABSTRACT FROM AUTHOR]

Aim: By contrast with drugs inhibiting the renin‐angiotensin‐aldosterone system (RAAS), diuretics stimulate renin release by the kidneys. Although plasma aldosterone (PA) is thought to be mainly regulated by RAAS activity, serum potassium has been shown to be an important factor in animal models and humans. Here we perform a systematic review and meta‐analysis of randomised controlled trials (RCT) in hypertension investigating the effects of diuretic therapy on PA and the correlation of change in PA with that of potassium and blood pressure (BP). Methods: Three databases were searched: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). Titles were first screened by title and abstract for relevance before full‐text articles were assessed for eligibility according to a predefined inclusion/exclusion criteria. Results: A total of 1139 articles were retrieved, of which 42 met the prespecified inclusion/exclusion criteria. The average standardised difference in mean PA was similar for all classes of diuretic: thiazide/thiazide‐like 0.299 (95% confidence interval [CI] 0.150, 0.447), loop 0.927 (0.37, 1.49), MRA/potassium‐sparing 0.265 (0.173, 0.357) and combination 0.466 (0.137, 0.796), Q = 6.33, P =.097. In subjects untreated with another antihypertensive, there was a significant relationship between change in PA and change in systolic BP but no relationship with the change in potassium. Conclusion: In RCTs of diuretic therapy in hypertension, there is an increase in PA with all classes of diuretic and no significant between‐class heterogeneity. Change in PA is not related with potassium but correlates with the change in BP in subjects untreated with another antihypertensive medication. [ABSTRACT FROM AUTHOR]

BackgroundPlasma coagulation Factor XIIa (Hageman factor; encoded by F12) and kallikrein (KAL or Fletcher factor; encoded by KLKB1) are proteases of the kallikerin-kinin system involved in converting the inactive circulating prorenin to renin. Renin is a key enzyme in the formation of angiotensin II, which regulates blood pressure, fluid and electrolyte balance and is a biomarker for cardiovascular, metabolic and renal function. The renin-angiotensin system is implicated in extinction learning in posttraumatic stress disorder.Methods & resultsActive plasma renin was measured from two independent cohorts- civilian twins and siblings, as well as U.S. Marines, for a total of 1,180 subjects. Genotyping these subjects revealed that the carriers of the minor alleles at the two loci- F12 and KLKB1 had a significant association with reduced levels of active plasma renin. Meta-analyses confirmed the association across cohorts. In vitro studies verified digestion of human recombinant pro-renin by kallikrein (KAL) to generate active renin. Subsequently, the active renin was able to digest the synthetic substrate angiotensinogen to angiotensin-I. Examination of mouse juxtaglomerular cell line and mouse kidney sections showed co-localization of KAL with renin. Expression of either REN or KLKB1 was regulated in cell line and rodent models of hypertension in response to oxidative stress, interleukin or arterial blood pressure changes.ConclusionsThe functional variants of KLKB1 (rs3733402) and F12 (rs1801020) disrupted the cascade of enzymatic events, resulting in diminished formation of active renin. Using genetic, cellular and molecular approaches we found that conversion of zymogen prorenin to renin was influenced by these polymorphisms. The study suggests that the variant version of protease factor XIIa due to the amino acid substitution had reduced ability to activate prekallikrein to KAL. As a result KAL has reduced efficacy in converting prorenin to renin and this step of the pathway leading to activation of renin affords a potential therapeutic target.

Introduction: In recent years hypertension has become an emerging condition in the young population. It has been proposed that the renin-angiotensin system plays an important role in regulation of blood pressure. We assessed whether activation of the intrarenal renin-angiotensin system occurs in hypertensive children and adolescents and what better reflects its activity: urine angiotensinogen (AGT) or urine renin (REN).Material and Methods: The study was conducted on a sample of 58 subjects with primary hypertension (HT) and 29 normotensive children and adolescents. We measured urine REN and AGT excretion and assessed the values in relation to blood pressure (BP) and other clinical parameters. Both REN and AGT values were calculated by urine creatinine: REN/cr. and AGT/cr., respectively.Results: We observed higher urine REN/cr. values in hypertensive subjects in comparison to the reference group (6.99 vs. 2.93, p = 0.003). Hypertensive participants showed positive correlations between urine REN/cr. and diastolic 24-hour BP (r = 0.42, p = 0.002) as well as between urine REN/cr. and urine AGT/cr. (r = 0.266, p = 0.044, respectively).Conclusions: Increased urine REN/cr. in hypertensive children and adolescents and its positive correlation with BP may indicate its important role in the pathogenesis of HT. Perhaps urine REN/cr. could be a marker of intrarenal renin-angiotensin system activity. Nevertheless, further research should be undertaken to confirm this observation. [ABSTRACT FROM AUTHOR]

Recent studies have shown that the long-term antihypertensive action of soluble epoxide hydrolase inhibition (sEH) in angiotensin-II (AngII)-dependent hypertension might be mediated by the suppression of intrarenal AngII levels. To test this hypothesis, we examined the effects of acute (2 days) and chronic (14 days) sEH inhibition on blood pressure (BP) in transgenic rats with inducible AngII-dependent hypertension. AngII-dependent malignant hypertension was induced by 10 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. BP was monitored by radiotelemetry. Acute and chronic sEH inhibition was achieved using cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid, given at doses of 0.3, 3, 13, 26, 60 and 130 mg/L in drinking water. At the end of experiments, renal concentrations of epoxyeicosatrienoic acids, their inactive metabolites dihydroxyeicosatrienoic acids and AngII were measured. Acute BP-lowering effects of sEH inhibition in I3C-induced rats was associated with a marked increase in renal epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids ratio and acute natriuresis. Chronic treatment with cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid in I3C-induced rats elicited dose-dependent persistent BP lowering associated with a significant reduction of plasma and kidney AngII levels. Our findings show that the acute BP-lowering effect of sEH inhibition in I3C-induced Cyp1a1-Ren-2 transgenic rats is mediated by a substantial increase in intrarenal epoxyeicosatrienoic acids and their natriuretic action without altering intrarenal renin-angiotensin system activity. Long-term antihypertensive action of cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid in I3C-induced Cyp1a1-Ren-2 transgenic rats is mediated mostly by suppression of intrarenal AngII concentration.

BackgroundAlthough variations in plasma renin activity (PRA) and aldosterone have been examined in whites and blacks, the association of these hormones with blood pressure in multiethnic populations has not been described.MethodsWe measured PRA and aldosterone in 1,021 participants in the Multi-Ethnic Study of Atherosclerosis not taking antihypertensives and examined the association between ethnicity and PRA/aldosterone and the association between PRA/aldosterone with systolic blood pressure (SBP).ResultsAverage age was 62 (SD = 9) years, and 49% of participants were women. Median PRA was 0.51 (interquartile range (IQR) = 0.29-0.87) ng/ml/hour, and median aldosterone was 12.6 (IQR = 9.1-17.1) ng/dl. After age and sex adjustment, compared with whites, blacks had 28% lower PRA and 17.4% lower aldosterone, and Hispanics had 20.1% higher PRA but similar aldosterone levels. After multivariable adjustment, compared with whites, only Hispanic ethnicity independently associated with higher PRA (0.18ng/ml/hour; 95% confidence interval (CI) = 0.06-0.31). Blacks had lower aldosterone (-1.7ng/dl; 95% CI = -3.2 to -0.2) compared with whites. After multivariable adjustment, PRA was associated with lower SBP in whites (-3.2mm Hg; 95% CI = -5.2 to -1.2 per standardized unit PRA), Chinese (-3.5mm Hg; 95% CI = -6.2 to -0.80 per standardized unit), and Hispanics (-2.3mm Hg; 95% CI = -4.1 to -0.6 per standardized unit) but not blacks. Aldosterone was associated with higher SBP only in Hispanics (2.5mm Hg; 95% CI = 0.4-4.5 per SD).ConclusionsCompared with whites, blacks have lower aldosterone and Hispanics have higher PRA. Aldosterone had significant associations with higher SBP in Hispanics compared with other groups, a finding that may suggest a different mechanism of hypertension.

Kidneys produce a number of substances that affect intrarenal blood circulation; however, the key system that regulates blood flow in both general and local circulation (including the renal circulation) is the renin-angiotensinaldosterone system (RAAS). Individual elements of the RAA system are synthesized in separate tissues of the body under the influence of specific local factors. The system functions as a whole due to mutual relations based on feedback and it consists of three basic elements: renin, angiotensin and aldosterone. The history of research on the RAA system dates back to the late 19th century. One of the important stages of exploring the mechanisms related to RAA system functioning was the publication (in 1898) of the results of research on the hypertensive effect on blood pressure of rabbit kidney extracts (containing renin). The observations from 1934 were of similar significance: the correlation between dog kidney ischaemia and the occurrence of hypertension was found. In the following years, the enzymatic properties and structure of renin and angiotensin peptides, resulting from the action of renin and the enzyme converting angiotensin I (Ang I) to its active form -- angiotensin II (Ang II), were clarified. The latter belongs to the most important regulators of aldosterone secretion. In 1939, it was proved that under the influence of renin blood pressure-rising peptides are formed. Consequently, it was documented that angiotensin was the cause of hypertension in animals with ischaemic kidney, and in 1954 the sequence of angiotensin I and II was described. In 1960-1961 systemic RAA occurrences were identified. However, to provide the insight of evolutionary significance of the RAA system for humans, the phylogenetic development of this enzyme-endocrine system in vertebrates should be investigated. The largest database of information regarding this system in the aforementioned group of animals is the research of Hirofumi Sokabe and Hiroko Nishimura, which, among others, is the basis for this manuscript. [ABSTRACT FROM AUTHOR]

BackgroundAlthough hypertension guidelines have utility in treating uncomplicated hypertension, they often overlook the pathophysiologic basis and heterogeneity of hypertension. This may explain the relatively poor hypertension control rates. A proposed approach is to guide addition and subtraction of medications using ambulatory plasma renin activity (PRA) values. To evaluate the heterogeneity of hypertension and the medication burden associated with it, we investigated medication usage in relation to PRA among hypertensive patients within a large ethnically diverse organization.MethodsA cross sectional data analysis was performed of hypertensive subjects with PRA measurements in the Kaiser Permanente Southern California database between 1 January 1998 and 31 October 2009.ResultsAmong 7,887 such patients 0, 1, 2, ≥3 medication usage was 16%, 20%, 24%, 40% respectively. PRA levels ranged 1000-fold. Across PRA quartiles (Q1 to Q4) ≥3 meds were prescribed to 50%, 40%, 34%, 37%. From low to high PRA quartiles there was no usage trend for angiotensin converting enzyme inhibitors (ACEIs)/ angiotensin receptor blockers (ARBs) (71%), but diuretics increased (52%, 53%, 57%, 68%), calcium channel blocker's (CCB) fell (56%, 53%, 51%, 42%), and β-blockers fell (77%, 61%, 49%, 41%). Moreover, systolic BP fell (146, 142, 140, 135 mm Hg), blood urea nitrogen (BUN) rose (16, 17, 18, 20 mg/dl), serum uric acid rose (6.1, 6.3, 6.5, 6.9 mg/dl), and chronic kidney disease rose (22%, 22%, 23%, 27%).ConclusionsPolytherapy was the norm for treating hypertension. Lower PRAs were associated with higher blood pressures and more medications. Higher PRAs were associated with lower pressures and fewer medications. The results indicate that opportunities exist to simplify antihypertensive therapy by using current ambulatory PRA levels to guide drug selections and subtractions.

In angiotensin II (Ang II)-dependent hypertensive rats there is an increased expression of proximal tubule angiotensinogen (AGT), collecting duct renin and angiotensin converting enzyme (ACE), which contributes to intratubular Ang II formation. Ang II acts on Ang II type 1 receptors promoting sodium retention and vasoconstriction. However concurrently, the ACE2-Ang-(1–7) axis and the expression of kallikrein and medullary prostaglandins counteract the effects of Ang II, promoting natriuresis and vasodilation. Human studies demonstrate that dietary potassium (K+) intake lowers blood pressure. In this report we evaluate the expression of AGT, ACE, medullary prorenin/renin, ACE2, kallikrein and cyclooxygenase-2 (COX-2) in Ang II-infused rats fed with high K+ diet (2%) for 14 days. Dietary K+ enhances diuresis in non-infused and in Ang II-infused rats. The rise in systolic blood pressure in Ang II-infused rats was attenuated by dietary K+. Ang II-infused rats showed increased renal protein levels of AGT, ACE and medullary prorenin and renin. This effect was attenuated in the Ang II + K+ group. Ang II infusion decreased ACE2 compared to the control group; however, K+ diet prevented this effect in the renal medulla. Furthermore, medullary COX-2 was dramatically induced by K+ diet in non-infused and in Ang II infused rats. Dietary K+ greatly increased kallikrein immunostaining in normotensive rats and in Ang II-hypertensive rats. These results indicate that a high K+ diet attenuates Ang II-dependent hypertension by preventing the induction of ACE, AGT and collecting duct renin and by enhancing medullary COX-2 and ACE2 protein expression in the kidney. [ABSTRACT FROM AUTHOR]

Soluble ST2, is a protein which acts as a decoy receptor for interleukin-33, and served as biomarker associated with left ventricular hypertrophy (LVH). Few data exist in evaluating the effects of anti-hypertensive agents on the role-played form ST2 on regression of LVH. This study was designed to compare the effects of captopril and valsartan on blood pressures, plasma renin and soluble ST2 levels and regression of LVH in hypertensive mice models. Twenty-four male mice (Mus musculus L), were divided into four groups, namely aquadest/control, L-NAME, L-NAME + captopril and L-NAME + valsartan groups respectively. Mice blood pressures were measured on day 14th after induction with L-NAME extract 1.75 mg/25g BW/day (pretreatment) and day 14th post treatment. Levels of plasma renin, sST2, and ventricular wall thicknesses reflecting LVHs, were measured on day 14th post treatment. Administration of L-NAME within 14 days resulted in making mice models to be hypertensive paralleled by an increase of Ventricular wall thickness. Treatment with captopril and valsartan lowered the blood pressures to normal level within the next 14 days. Valsartan and captopril treatment induced a significant decrease of plasma renin level. Valsartan, but not for captopril treatment prevented wall thickness increase (p < 0.05), while plasma sST2 was not able to mirroring this effect. Captopril and valsartan had similar effect in lowering plasma renin level and blood pressure, but sST2 seems to be not involved in LVH regression obtained in hypertensive mice models after blocking renin-angiotensin system. [ABSTRACT FROM AUTHOR]

The central nervous system plays an important role in essential hypertension in humans and in animal models of hypertension through modulation of sympathetic activity and Na and body fluid homeostasis. Data from animal models of hypertension suggest that the renin-angiotensin system in the subfornical organ (SFO) of the brain is critical for hypertension development. We recently reported that the brain (pro) renin receptor (PRR) is a novel component of the brain reninangiotensin system and could be a key initiator of the pathogenesis of hypertension. Here, we examined the expression level and cellular distribution of PRR in the SFO of postmortem human brains to assess its association with the pathogenesis of human hypertension. Postmortem SFO tissues were collected from hypertensive and normotensive human subjects. Immunolabeling for the PRR and a retrospective analysis of clinical data were performed. We found that human PRR was prominently expressed in most neurons and microglia, but not in astrocytes, in the SFO. Importantly, PRR levels in the SFO were elevated in hypertensive subjects. Moreover, PRR immunoreactivity was significantly correlated with systolic blood pressure but not body weight, age, or diastolic blood pressure. Interestingly, this correlation was independent of antihypertensive drug therapy. Our data indicate that PRR in the SFO may be a key molecular player in the pathogenesis of human hypertension and, as such, could be an important focus of efforts to understand the neurogenic origin of hypertension. [ABSTRACT FROM AUTHOR]