Renin-angiotensin II-aldosterone System Research Articles

Transient secondary pseudo-hypoaldosteronism in infants with urinary tract infections: systematic literature review

Infants with a congenital anomaly of the kidney and urinary tract sometimes present with hyponatremia, hyperkalemia, and metabolic acidosis due to under-responsiveness to aldosterone, hereafter referred to as secondary pseudo-hypoaldosteronism. The purpose of this report is to investigate pseudo-hypoaldosteronism in infant urinary tract infection. A systematic review was conducted following PRISMA guidelines after PROSPERO (CRD42022364210) registration. The National Library of Medicine, Excerpta Medica, Web of Science, and Google Scholar without limitations were used. Inclusion criteria involved pediatric cases with documented overt pseudo-hypoaldosteronism linked to urinary tract infection. Data extraction included demographics, clinical features, laboratory parameters, management, and course. Fifty-seven reports were selected, detailing 124 cases: 95 boys and 29 girls, 10 months or less of age (80% of cases were 4 months or less of age). The cases exhibited hyponatremia, hyperkalemia, acidosis, and activated renin-angiotensin II-aldosterone system. An impaired kidney function was found in approximately every third case. Management included antibiotics, fluids, and, occasionally, emergency treatment of hyperkalemia, hyponatremia, or acidosis. The recovery time averaged 1 week for electrolyte, acid–base imbalance, and kidney function. Notably, anomalies of the kidney and urinary tract were identified in 105 (85%) cases.Conclusions:This review expands the understanding of overt transient pseudo-hypoaldosteronism complicating urinary tract infection. Management involves antimicrobials, fluid replacement, and consideration of electrolyte imbalances. Raising awareness of this condition within pediatric hospitalists is desirable.What is Known:• Infants affected by a congenital anomaly of the kidney and urinary tract may present with clinical and laboratory features resembling primary pseudo-hypoaldosteronism.• Identical features occasionally occur in infant urinary tract infection.What is New:• Most cases of secondary pseudo-hypoaldosteronism associated with a urinary tract infection are concurrently affected by a congenital anomaly of the kidney and urinary tract.• Treatment with antibiotics and parenteral fluids typically results in the normalization of sodium, potassium, bicarbonate, and creatinine within approximately 1 week.

Green tea could improve elderly hypertension by modulating arterial stiffness, the activity of the renin/angiotensin/aldosterone axis, and the sodium-potassium pumps in old male rats.

Hypertension is a major health problem common in the elderly people. Green tea is a popular beverage recommended in folk medicine for lowering blood pressure. However, the molecular mechanisms involved in the antihypertensive effects of green tea are not fully understood. Therefore, the aim of this study was to investigate the antihypertensive effects of green tea on high-salt diet-induced hypertension in old male rats. Forty old male rats were divided into five groups: control, hypertensive, and hypertensive-green tea (2, 4, and 6g/kg). Heart rate (HR) and systolic blood pressure (SBP) were measured. Cardiac and renal histology were also performed. Lipid profile, NO, angiotensin II (Ang II), and aldosterone were determined, and the expression of eNOS, ATIR and ATIIR, aldosterone receptor, and Atp1a1 were measured. Green tea could significantly decrease HR and SBP, lipid profiles, renin-angiotensin II-aldosterone system activity, and Ang II signaling in kidney tissue of hypertensive rats (p< .01). It also increased Atp1a1, Nrf2, and eNOS expression along with antioxidant enzymes activity and NO concentration (p< .05) and decreased NF-ĸB and iNOS expression and IL-1β levels in the heart, kidneys, and aorta of rats with hypertension. It can be concluded that green tea can improve salt-induced blood pressure by modulating the function of the renin-angiotensin-aldosterone system, enhancing the synthesis of nitric oxide in the endothelium, increasing antioxidant activity and suppressing inflammation in the heart and kidney, improving the expression of the sodium-potassium pump, and reduction in serum lipids and glucose in aged male rats. PRACTICAL APPLICATIONS: The results of this study showed that green tea could improve hypertension in elderly rats by modulating (1) the expression of the sodium-potassium pump in the heart, kidney, and aortic tissues, (2) the activity of the renin-angiotensin II-aldosterone system in kidney, (3) enhancing antioxidant and anti-inflammatory activities in the heart, aorta, and kidneys, (4) enhancing the synthesis of nitric oxide in the endothelium, and (5) lowering lipid profile. The results of these studies show that the consumption of green tea and its products can be a good candidate for the prevention of cardiovascular diseases such as hypertension in the elderly. In addition, attention to its bioactive compounds can be considered by researchers as an independent therapeutic strategy or adjunctive therapy for the treatment of hypertension.

Adherence to long-term use of renin-angiotensin II-aldosterone system inhibitors in children with chronic kidney disease

BackgroundAlthough renin-angiotensin II-aldosterone system inhibitor (RASI) use for renal protection is well-documented, adherence to RASI therapy in the pediatric population is unclear. This study aimed to evaluate patient characteristics associated with adherence to chronic RASI use in patients with childhood chronic kidney disease (CKD).MethodsChildhood CKD was identified using ICD-9 codes in the population-based, Taiwan national health insurance research database between 1997 and 2011. Patients continuously receiving RASIs for ≥3 months without interruption > 30 days after CKD diagnosis were defined as incident users. Medication adherence was measured as the proportion of days covered (PDC) by RASI prescription refills during the study period. Multivariate logistic regression was employed to assess the odds for adherence (PDC ≥80%) to RASI refills.ResultsOf 1271 incident users of RASI chronic therapy, 16.9% (n = 215) had PDC ≥80%. Compared to the group with PDC < 80%, patients in the high adherence group more often had proteinuria (aOR [adjusted odds ratio]1.93; 95%CI [confidence interval], 1.18–3.17), anemia (aOR, 1.76; 95% CI, 1.20–2.58), and time to start of chronic use > 2 years (aOR, 1.12; 95%CI, 1.06–1.19). Odds of being non-adherent were increased by hypertension and older ages (comparing to < 4 years) at start of chronic use, 9–12 years (aOR, 0.38; 95%CI, 0.17–0.82), 13–17 years (aOR, 0.45; 95%CI, 0.22–0.93),≥18 years (aOR, 0.34; 95%CI 0.16–0.72) and males (aOR, 0.68; 95%CI, 0.49–0.94).ConclusionsThe rate of RASI prescription refilling adherence was relatively low and associated with CKD-specific comorbid conditions. This study identifies factors associated with low adherence and highlights the need to identify those who should be targeted for intervention to achieve better blood pressure control, preventing CKD progression.

Renin-angiotensin II-aldosterone system blockers and time to renal replacement therapy in children with CKD.

Clinical care decisions to treat chronic kidney disease (CKD) in a growing child must often be made without the benefit of evidence from clinical trials. We used observational data from the Chronic Kidney Disease in Children cohort to estimate the effectiveness of renin-angiotensin II-aldosterone system blockade (RAAS) to delay renal replacement therapy (RRT) in children with CKD. A total of 851 participants (median age: 11years, median glomerular filtration rate [GFR]: 52ml/min/1.73m2, median urine protein to creatinine ratio: 0.35mg/mg) were included. RAAS use was reported at annual study visits. Both Cox proportional hazards models with time-varying RAAS exposure and Cox marginal structural models (MSM) were used to evaluate the effect of RAAS use on time to RRT. Analyses were adjusted or weighted to control for age, male sex, glomerular diagnosis, GFR, nephrotic range proteinuria, anemia, elevated blood pressure, acidosis, elevated phosphate and elevated potassium. There were 217 RRT events over a 4.1-year median follow-up. At baseline, 472 children (55%) were prevalent RAAS users, who were more likely to be older, have a glomerular etiology, have higher urine protein, be anemic, have elevated serum phosphate and potassium, take more medications, but less likely to have elevated blood pressure, compared with non-users. RAAS use was found to reduce the risk of RRT by 21% (hazard ratio: 0.79) to 37% (hazard ratio: 0.63) from standard regression adjustment and MSM models, respectively. These results support inferences from adult studies of a substantial benefit of RAAS use in pediatric CKD patients.

Mitochondrial reactive oxygen species (ROS) as signaling molecules of intracellular pathways triggered by the cardiac renin-angiotensin II-aldosterone system (RAAS)

Mitochondria represent major sources of basal reactive oxygen species (ROS) production of the cardiomyocyte. The role of ROS as signaling molecules that mediate different intracellular pathways has gained increasing interest among physiologists in the last years. In our lab, we have been studying the participation of mitochondrial ROS in the intracellular pathways triggered by the renin-angiotensin II-aldosterone system (RAAS) in the myocardium during the past few years. We have demonstrated that acute activation of cardiac RAAS induces mitochondrial ATP-dependent potassium channel (mitoKATP) opening with the consequent enhanced production of mitochondrial ROS. These oxidant molecules, in turn, activate membrane transporters, as sodium/hydrogen exchanger (NHE-1) and sodium/bicarbonate cotransporter (NBC) via the stimulation of the ROS-sensitive MAPK cascade. The stimulation of such effectors leads to an increase in cardiac contractility. In addition, it is feasible to suggest that a sustained enhanced production of mitochondrial ROS induced by chronic cardiac RAAS, and hence, chronic NHE-1 and NBC stimulation, would also result in the development of cardiac hypertrophy.

T-type Ca2 + signalling downregulates MEK1/2 phosphorylation and cross-talk with the RAAS transcriptional response in cardiac myocytes

Cardiac dysfunction is often associated with an increase in the activity of the renin–angiotensin II–aldosterone system (RAAS). Here, we highlight the cross-talk between the Ca2+ signalling generated by cardiac T-type current (ICaT) and RAAS signalling.Neonatal rat cardiomyocytes exposed to aldosterone, angiotensin II or aldosterone plus angiotensin II co-treatment (AA) show an increase in ICaT density, with no cumulative effect of the AA co-treatment. AA increases the amount of T-type channel Cav3.1 mRNA in a time-dependent manner. Angiotensin II increases Cav3.1 mRNA stability, whereas aldosterone increases the transcriptional activity of the Cav3.1 gene promoter. However, in AA-treated cells, angiotensin II decreases aldosterone-induced promoter activity, and aldosterone decreases angiotensin II-induced mRNA stability. The mitogen-activated protein kinase kinase (MEK1/2), which is synergically phosphorylated in AA-treated cells, alters the translocation of glucocorticoid receptors (GR) into the nucleus and attenuates aldosterone-induced promoter activity. In contrast, MEK1/2 has no effect on the NFkB-induced increase in Cav3.1 mRNA and MEK1/2 promoted CREB-target gene transcription. Aldosterone and AA-induced ICaT signalling result in a time-dependent activation of the phosphatase PP2A, which dephosphorylates MEK1/2 and CREB. Finally, angiotensin II alone also activates PP2A, which targets MEK1/2, but this activation is independent of ICaT calcium signalling and has no effect on CREB phosphorylation.In conclusion, our data demonstrate the cross-talk between a GR-mediated aldosterone response, angiotensin II and the ICaT signalling pathways and identify MEK1/2 as a point of connection. This cross-talk results in the fine control of GR- and/or CREB-target gene expression.

Exercise Training Reduces Age‐Dependent Elevation of Angiotensin II Type 1 receptor and NAD(P)H Oxidase

Fibrosis in the aging heart impedes diastolic filling and increases arrhythmias. Previously, we demonstrated that exercise training (ET) reduced collagen I fibrosis and oxidative stress in the aging heart. Recent studies show that NAD(P)H oxidases (Nox) could be an important source of oxidative stress during the aging process, activated by renin‐angiotensin II‐aldosterone system (RAAS). Given that Nox and RAAS may elicit collagen accumulation in the aging heart, we tested the hypothesis that ET would alleviate age‐related upregulation of Nox (p47phox) and RASS (angotensin II receptor 1: ATR1) markers. Young (3 mo) and old (31 mo) FBNF1 rats were assigned into sedentary (YS, OS) and exercise (YE, OE) groups, with ET rats training on a treadmill 45 min/d, 5 d/wk for 12 wk. ET diminished web‐like geometry of connective tissue and large cardiomyocytes in the old age group. Aging increased p47phox–positive staining and protein expression 78.4% (p&lt;.032) in the LV, while OE displayed lower p47phox‐positive staining, with protein abundance trending lower (−46.6%). gp91phox levels in OS trended higher 22.8% than YS. ATR1 was significantly elevated with age (+36.6%, p&lt;.02), but was not significantly blunted with ET. Results indicate that exercise training may provide significant protection against Nox upregulation and thus fibrosis, while upstream regulation by ATR1 remains uncertain.

Aldosterone‐receptor antagonism as a potential therapeutic option for atrial fibrillation

Recent research provided important insights into the development of atrial fibrillation (AF)-maintaining substrate and suggested targeting of the underlying molecular mechanisms, 'upstream' of the electrical aspects of AF, as a novel strategy for AF treatment ('upstream' therapy). Upstream therapies for AF include drugs targeting the renin-angiotensin II-aldosterone system (angiotensin converting enzyme inhibitors and AT(1) receptor antagonists and aldosterone antagonists), statins, steroids and omega-3 fatty acids (fish oil). Aldosterone causes volume retention, cardiac hypertrophy and fibrosis, and systemic inflammation and coagulation that promote AF development and its complications and blockade of aldosterone receptors with spironolactone or eplerenone suppresses inducible AF. Although the clinical impact of spironolactone treatment requires validation in randomized clinical trials in AF patients, further understanding of the molecular mechanisms by which aldosterone causes atrial remodelling is likely to lead to development of novel therapeutic approaches to AF.

Systemic Hypertension and Proteinuria in Childhood Chronic Renal Parenchymal Disease

A variety of chronic kidney diseases tend to progress towards end-stage kidney disease. Progression is largely due to factors unrelated to the initial disease, including systemic hypertension and proteinuria. Drugs that block the renin-angiotensin II-aldosterone system, either ACE inhibitors or angiotensin II receptor antagonists, reduce both BP and proteinuria and appear superior to a more conventional antihypertensive treatment regimen in preventing progression to end-stage kidney disease. The most recent recommendations state that the BP goal in children with chronic kidney disease is the corresponding 90th centile for body height, age, and gender. Since satisfactory BP control is often not achieved, the mnemonic acronym DELTAREPROSI was generated to recall the following tips for the practical management of hypertension and proteinuria in childhood chronic renal parenchymal disease: DEfinition of hypertension and Low blood pressure TArget in REnal disease (90th centile calculated by means of simple formulas), potential of drugs inhibiting the REnin-angiotensin II-aldosterone system in hypertension and PROteinuria, advantages of SImplified treatment regimens and escalating the doses every SIx weeks.

Prostaglandins in congestive heart failure and the effects of nonsteroidal anti-inflammatory drugs

With the failure of the heart as a pump, there ensues a series of neurohumoral compensations that defend organ perfusion at the expense of alterations in cardiac filling pressures and the distribution of blood flow to various regional circulations. Activation of the sympathetic nervous system and the renin-angiotensin II-aldosterone system and increases in circulating arginine vasopressin maintain arterial blood pressure by producing systemic arteriolar vasoconstriction and the renal retention of salt and water. Constriction of the efferent arterioles in the kidney by angiotensin II and norepinephrine promotes reabsorption of glomerular filtrate in the peritubular capillaries and maintains glomerular filtration in the face of declines in glomerular plasma flow and the glomerular permepbility-surface area ultrafiltration coefficient. In resting, sodiumreplete, conscious animals and humans, pharmacologic inhibitiop of renal cyclo-oxygenase by nonsteroidal anti-inflammatory drugs has little or no effect on renal hemodynamics. However, electrical or reflex stimulation of the renal nerves, intrarenal infusion of angiotensin II, or infusion of arginine vasopressin stimulates the release of vasodilator prostaglandins from the kidneys. In sodium-depleted animals or humans, and when cardiac output decreases, there is an increase in total peripheral vascular resistance but little change in renal vascular resistance. Increased renal synthesis of vasodilator prostaglandins (presumably by the blood vessels) maintains renal blood flow despite increased release of renin and norepinephrine from the kidneys. In these situations, pharmacologic inhibition of renal cyclo-oxygenase is accompanied by marked reductions in renal blood flow and glomerular filtration rate. When this occurs in patients with advanced heart failure, reversible oliguric renal failure may result. In this setting, cyclo-oxygenase inhibition may also increase arterial pressure and induce additional depression of cardiac function. Recent data indicate that blood vessels have the capacity to synthesize the sulfidopeptide leukotrienes C 4, D 4, and E 4, which can constrict peripheral and renal blood vessels and alter vascular permeability. The vascular cell types responsible for leukotriene C 4 synthesis and the potential roles of these vasoactive eicosanoids in kidney and other regional circulations are currently under study.

Role of renin and aldosterone suppression in the antihypertensive mechanism of clonidine

The hypothesis that clonidine decreases blood pressure by suppression of the renin-angiotensin II-aldosterone system was investigated in 20 hypertensive patients during a constant sodium and potassium intake. A significant decrease in mean arterial pressure (MAP), from 123 ± 3 to 102 ± 3 mm Hg (P < 0.001) was observed in 15 patients (responders) during treatment with clonidine. In these patients, plasma renin activity (PRA) was decreased by clonidine from 9.9 ± 3.9 to 5.4 ± 1.6 ng/ml/hour (P < 0.05). The decrease in MAP correlated with the decrease in PRA (r = 0.685, P < 0.02) and with the pretreatment PRA (R = 0.596, P < 0.05). The aldosterone excretion was decreased by clonidine by 29 per cent (from 16 ±4 to 11 ± 2 μg/24 hours), but not significantly. However, the changes in PRA were significantly correlated with the changes in aldosterone (r = 0.645, P < 0.05). Among the responders to clonidine, those with the higher pretreatment PRA levels showed the greatest fall in blood pressure. A common characteristic of the nonresponders to clonidine (five patients) was the presence of moderate to severe renal insufficiency. Moreover, in the nonresponders, PRA and urinary aldosterone were not significantly suppressed by clonidine. In order to evaluate further the role of renin suppression as an antihypertensive mechanism during clonidine treatment, the renin (angiotensin II) dependency of hypertension was tested prior to the administration of clonidine by giving an infusion of the angiotensin II competitive antagonist, saralasln to eight patients. In four of the eight patients blood pressure was decreased by both clonidine and saralasin, whereas in three patients clonidine decreased MAP, but saralasin elicited a pressor response. Finally one nonresponder to clonidine exhibited a depressor response to saralasin. Thus, clonidine decreased blood pressure in patients with nonrenin-dependent hypertension. Over-all results indicate that although the decrease in blood pressure is related to renin suppression during treatment with clonidine, another antihypertensive mechanism (or mechanisms) still exists in hypertension without renin dependency.

Inhibition of transmembrane K transfer in ureter-ligated dogs infused with KCl

In anuric dogs loaded with K by infusion with 2 meq KCl/kg per h until prelethal hyperkalemic cardiotoxicity appears, the extent of transmembrane K transfer depends on the origin of the anuria. Animals with bilateral ureter ligation transfer a mean of 1.2 meq/kg to intracellular fluid, while those with bilateral nephrectomy transfer more than 2.5 times as much (3.1 meq/kg). Further, if dogs with functioning kidneys are ureter ligated or nephrectomized after approximately 45 min of K loading, K transfer ultimately falls as infusion continues. The fall is precipitate and over 90% in ligated animals; but it is gradual, and only 10% in those that are nephrectomized. Finally, K transfer, because of the absence of insulin, is negligible in K-loaded pancreatectomized dogs with bilateral ureter ligation, but fairly substantial in pancreatectomized animals with bilateral nephrectomy. The data suggest that ureter ligation and hyperkalemia activate a renal mechanism that interferes with the transfer of infused K to intracellular fluid. The mechanism may involve the renin-angiotensin II-aldosterone system to a limited degree.