Renin-angiotensin-aldosterone System Pathway Research Articles

New insights into prostate Cancer from the renin-angiotensin-aldosterone system.

Prostate cancer is among the most common malignancies found in men, with multifactorial changes occurring altogether to disrupt the pathophysiology of this gland. The Renin-Angiotensin-Aldosterone System (RAAS) is an extensively studied pathway that has newly attributed fundamental roles in cancer biology that impact cell growth, migration, metastasis, and death. These processes are significantly influenced by various components of the RAAS, including prorenin, AT1R, AT2R, and Ang 1–7/Mas receptors. Although the pathophysiology of prostate cancer is complex, targeting the RAAS shows promise as a therapeutic approach. RAAS dysregulation is evident in prostate cancer, and treatments traditionally used for cardiovascular diseases are being explored for cancer therapy. The RAAS pathway has significant effects on the formation of new blood vessels (angiogenesis), the spread of cancer cells to other parts of the body (metastasis), and cell proliferation. In this pathway, angiotensin II and its receptors have crucial functions. Angiotensin II stimulates angiogenesis and cell proliferation through the AT1R, whereas the AT2R has the opposite effect by inhibiting cell growth. Additional pathways involving ACE2/Ang 1–7/Mas also provide potential targets for therapeutic intervention, mitigating the impact of the traditional ACE/Angiotensin II/AT1R pathway. The components of the RAAS influence multiple signalling pathways, such as Androgen Receptor (AR), NF-κB, and PI3K/AKT/mTOR, which enhances our understanding of how it contributes to the progression of prostate cancer. This also provides new possibilities for therapeutic interventions.

Abstract We140: Age-Dependent miR-34a and AGTRAP Cross-Modulation: a Novel Mechanism of Vascular Aging

Background: Renin-Angiotensin Aldosterone System (RAAS) activation plays a central role in vascular aging, leading to structural and functional alterations including vascular smooth muscle cell (VSMC) proliferation, migration and secretion of extracellular matrix and inflammatory molecules. The age-associated increase in Angiotensin II (Ang II) expression enhances AT1-receptor activity and determinates a pro-fibrotic and pro-inflammatory phenotype. Further, miR-34a expression is modulated by aging and increases in different tissues, including the mouse aorta, but no direct miR-34a target has been identified in the RAAS pathway that sustains age-dependent increase of pro-inflammatory signaling. Aims: The aim of our study is to evaluate the potential interaction between miR-34a and RAAS signaling in VSMCs. Methods and Results: miR-34a expression exhibited an age-dependent increase in Rhesus Monkey (8- to 26-year-old) and rat central arteries (8- and 30-month-old). In silico analysis indicated that AT1R-associated protein (AGTRAP), a negative modulator of AT1R signaling, is a potential miR-34a target suggesting that the age-dependent increase in miR-34a in the arterial vascular wall may decrease AGTRAP expression in arterial VSMC. Ang II enhanced miR-34a expression in 30-month-old rat and in human aorta SMCs (HASMCs), whereas AGTRAP and Sirtuin-1 (SIRT1) mRNA and protein level decreased. Immunohistochemistry analysis showed a decrease of AGTRAP in 18-month-old miR-34a knock-out mice compared to 2-month-old mice. By luciferase assay, we demonstrated that AGTRAP is a direct miR-34a target. Moreover, AGTRAP and SIRT1 decreased in HASMCs infected with miR-34a-encoding lentivirus and this effect was partially rescued in AGTRAP/miR-34a co-infected cells. Finally, pro-inflammatory genes IL-6, COX-2, MCP-1 and MFG-E8 expression was upregulated in Ang II-treated and miR-34a overexpressing HASMCs, and this effect was abolished in AGTRAP/miR-34a co-transfected cells. Conclusions: Our results show cross-modulation between miR-34a and AGTRAP. MiR-34a targeting AGTRAP increases the expression of pro-inflammatory molecules in VSMCs and represents a novel mechanism that modulates RAAS signaling in vascular aging. Statement: This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.

#977 Etelcalcetide improve left ventricular hypertrophy by suppressing the renin-angiotensin-aldosterone system and cardiac fibroblast growth factor 23

Abstract Background and Aims Calcimimetics are allosteric activators of the calcium-sensing receptor (CaSR) and are employed as therapeutic agents for managing secondary hyperparathyroidism in chronic kidney disease (CKD) patients undergoing dialysis. Although they have shown potential in reducing cardiovascular diseases and suppressing left ventricular hypertrophy (LVH), the mechanisms underlying these effects are not fully elucidated. In this study, we focused on exploring the mechanisms behind the suppression of LVH by calcimimetics using CKD, LVH, and CKD+LVH model rats. Specifically, we investigated the impact on CKD-mineral bone disorder (CKD-MBD) parameters, the renin-angiotensin-aldosterone system (RAAS), and calcineurin/nuclear factor of activated T cells (CaN/NFAT) pathway. Method In this study, we used etelcalcetide (ET) as a calcimimetic agent. At 8 weeks of age, LVH was induced in rats through transverse aortic coarctation, and CKD was induced by 5/6 nephrectomy at 9 and 10 weeks of age. The rats were divided into the four main groups: the sham group, the CKD group, the LVH group, and the CKD+LVH group. Each of the latter three groups were further subdivided into a vehicle-treated group and an ET-treated group for a duration of eight weeks. At 19 weeks of age, echocardiography was conducted on all rats prior to sacrifice. Subsequently, the rats were sacrificed, and blood and urine analyses, mRNA expression analysis, and renal histological analysis were performed. We evaluated LVH, CKD-MBD, RAAS, and CaN/NFAT pathways across these seven groups. Results In both the CKD and CKD+LVH groups, serum levels of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) were significantly elevated, and these elevations were mitigated by ET. However, in the LVH group, serum PTH and FGF23 levels were not elevated, and ET did not induce any changes. No significant alterations in serum levels of phosphorus, calcium, 25(OH)vitamin, and 1,25(OH)2vitaminD levels due to ET were observed in any of the groups. Interestingly, ET suppressed the increase in myocardial weight/body weight ratios and the area of cardiomyocytes not only in the CKD and CKD+LVH group but also in the LVH group, despite no changes in serum PTH and FGF23 levels. Regarding the RAAS, ET attenuated the increase in serum aldosterone levels, expressions of cardiac angiotensin-converting enzyme (ACE), cardiac angiotensinogen, and cardiac angiotensin II in the LVH group and the CKD+LVH group. The expression of cardiac FGF23, which increased in the LVH group and the CKD+LVH group, was decreased by ET. Moreover, there was a significant correlation between cardiac RAAS parameters and cardiac FGF23 expressions. No alteration was observed in the CaN/NFAT pathway in response to ET. Conclusion Our findings indicated that ET effectively suppressed LVH in the CKD group and the CKD+LVH group, and it was also effective in the LVH group, independent of changes in serum CKD-MBD parameters. This suggests that ET may exert its LVH-suppressing effects through the RAAS pathway and cardiac FGF23.

Angiotensin-Converting Enzyme (ACE) Insertion/Deletion (I/D) Polymorphism as a Conjoint Regulator of Coagulation, Fibrinolytic, and RAAS Pathway in Infertility and Associated Pregnancy Complications.

Despite the increase in assisted reproductive technologies, the high rates of infertility and pregnancy complications are a major concern to infertility specialists worldwide. Infertility may be attributed to pregnancy complications like thrombophilia, preeclampsia and fibrin-induced recurrent pregnancy loss (RPL). Renin-angiotensin-aldosterone system (RAAS) directly or indirectly causes preeclampsia and thrombophilia through the fibrinolytic pathway that ultimately leads to RPL or infertility. The underlying mechanisms of this interaction are still unclear. The present comprehensive review is intended to demonstrate the role and interaction of RAAS and fibrinolytic pathways in pregnancy complications. How this interaction can induce pregnancy complications, and ultimately infertility, is also discussed in the light of current evidence. This study also presents common markers that link RAAS and fibrinolytic processes in developing thrombophilia, preeclampsia and RPL. The common link in these pathways is ACE gene I/D polymorphism. Apart from ACE, PAI-1, VIIa, XIIa, AT1R, AT1AA, and TF are common molecules that can delineate the underlying causes of pregnancy complications and infertility.

Abstract 13442: Renin-Angiotensin Metabolite Profiling via LC-MS/MS Reveals Sex Dependent Differences Induced by High-Salt Diet in Dahl-S Rats

Background: Understanding how sex influences the pathophysiology of cardiovascular and renal disease may enhance precision medicine approaches that account for sex specific biologic differences in these diseases. Nevertheless, characterization of preclinical models often fail to account for the role of sex on important pathophysiologic mechanisms. The renin-angiotensin-aldosterone system (RAAS) plays a central role in the development and progression of cardiovascular and renal disease. In addition to the classic RAAS pathway, an alternative RAAS pathway produces angiotensins (e.g. Ang [1-7]) that can counteract classical RAAS hormones such as Angiotensin (Ang) II. We hypothesized that RAAS profiling in a high-salt fed Dahl-S rat model would reveal significant sex differences in both classic and alternative RAAS pathways. Methods/Results: Ten week-old male and female Dahl-S rats were fed either 0.2% salt normal chow (SS-NC), or 8% high-salt diet (SS-HS) for eight weeks (n=6-8/group). Equilibrium RAAS profiling via LC-MS/MS was performed in lithium heparin plasma samples. In response to high-salt diet, both male and female SS-HS rats had significant (p<0.05) reductions vs. their respective SS-NC controls in plasma aldosterone (-93% in male SS-HS, -97% in female SS-HS), Ang II (-71% in male SS-HS, -41% in female SS-HS), Ang IV (-79% in male SS-HS, -54% in female SS-HS) as well as calculated plasma renin activity (-67% in male SS-HS, -42% in female SS-HS), although the magnitude of reduction was generally greater in males vs. females. Alternatively, only male SS-HS rats had significant (p<0.05 vs. SS-NC) reductions in plasma Ang I (-63%), Ang III (-66%), as well RAAS metabolites of the alternative RAS axis, Ang [1-5] (-58%) and Ang [1-7] (-70%) vs. SS-NC. Comparing female vs. male SS-HS rats, females had significantly (p<0.01 vs. male) increased levels of angiotensins of the classic RAS pathway, such as Ang I (113%), Ang II (104%), Ang III (150%) and Ang IV (265%) after high-salt diet. Conclusion: High-salt diet induces significant sex-dependent differences in both classic and alternative RAAS pathways of Dahl-S rats and may provide important insight into the sex-dependent differences of cardiovascular and renal injury seen in this model.

A Narrative Review of the Renin-Angiotensin-Aldosterone System in the Placenta and Placental Bed of HIV Infected Women of African Ancestry with Preeclampsia.

Purpose of ReviewBoth HIV infection and preeclampsia (PE), a pregnancy-specific disorder of hypertension and multi-system organ involvement, have high prevalence rates especially in low-to-middle-income countries. The immunoexpression of specific renin-angiotensin-aldosterone system (RAAS) receptors in the placenta and placental bed interface may forecast the risk of PE.Recent FindingsPreeclampsia is a leading risk factor for mortality worldwide and remains a challenge in HIV-infected individuals especially those on antiretroviral therapy (ART). Irregular RAAS stimulation may be linked to the pathophysiology of hypertension in HIV infection and in PE. The AT1 receptor is expressed across all trimesters of pregnancy, within placental tissue, eliciting vasoconstriction. This increased expression is associated with the severity of PE, implying that the increased expression may be involved in the pathogenesis of this pregnancy disorder. The AT2 receptor expression in normotensive pregnancies was shown to be lower as compared to non-pregnant individuals. Furthermore, in the PE placental bed, the AT2 receptor is the predominant receptor subtype and is found in extravillous trophoblast cells where they facilitate vasodilation. However, AT4R in placentae of PE pregnancies are found to be significantly reduced compared to normotensives pregnancies.SummaryThe data on the role played by the RAAS pathway in pregnancy is conflicting. Investigation into a tissue-based RAAS with emphasis on immune-expression within the placenta and placental bed may help resolve this conundrum.

The chemical profiling of aqueous soluble fraction from Lagopsis supina and its diuretic effects via suppression of AQP and RAAS pathways in saline-loaded rats

Ethnopharmacological relevanceLagopsis supina (Steph.) Ik. -Gal. ex Knorr. has been widely used as a remedy treatment for diuresis and edema in China over 2500 years. Our previous results showed that the aqueous soluble fraction from L. supina (LSB) possessed acute diuretic effect. Aim of the studyThe aim of this study was to appraise the acute (6 h) and prolonged (7 d) diuretic effects, underlying mechanisms, and chemical profiling of LSB. Materials and methodsThe chemical profiling of LSB was performed by ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-qTOF-MS/MS). Then, oral administration of LSB (40, 80, 160 and 320 mg/kg) and furosemide (10 mg/kg) once daily for 7 consecutive days to evaluate the diuretic effects in saline-loaded rats. The body weight, food consumption, and water intake were recorded once daily. The urinary volume, pH and electrolyte concentrations (Na+, K+, Cl−, and Ca2+) were measured after administration drugs for acute and prolonged diuretic effects. In addition, the serum levels of Na+-K+-ATPase, angiotensin II (Ang II), anti-diuretic hormone (ADH), aldosterone (ALD), atriopeptin (ANP), aquaporins (AQPs)-1, 2 and 3 were determined by ELISA kits. The mRNA expressions and protein levels of AQPs-1, 2 and 3 were analyzed by real-time quantitative PCR and Western blot assays, respectively. Results30 compounds were identified in LSB based on accurate mass and MS/MS fragmentation compared to literature, among which phenylpropanoids and flavonoids could be partly responsible for the major diuretic effect. Daily administration of LSB (160 or 320 mg/kg) prominently increased urinary excretion volume after the 2 h at the first day of treatment, remaining until the 7th day. LSB did not cause Na+ and K+ electrolyte abnormalities, and has minor effect on Cl− and Ca2+ concentrations at 320 mg/kg. Furthermore, LSB observably suppressed renin-angiotensin-aldosterone system (RAAS) activation, including decreased serum levels of Ang II, ADH, and ALD, and prominently increased serum level of ANP in rats. LSB treatment significantly down-regulated the serum levels, mRNA expressions and protein levels of AQP1, AQP2, and AQP3. ConclusionLSB has a prominent acute and prolonged diuretic effects via suppression of AQP and RAAS pathways in saline-loaded rats, and support the traditional folk use of this plant. Taken together, LSB might be a potential diuretic agent.

RENIN-INHIBITORY BIOACTIVE PEPTIDES WITH ANTIHYPERTENSIVE PROPERTY: A REVIEW

Blood pressure is regulated by the renin angiotensin aldosterone system (RAAS). Renin-catalyzed conversion of angiotensinogen to angiotensin I is the rate-limiting step of the RAAS pathway, which arguably makes renin a better target for prevention, treatment and management of hypertension than Angiotensin-Converting Enzyme (ACE). Hydrolysis of food proteins releases bioactive peptides that can interact with receptors, enzymes and molecules in the organism to promote health. Several studies have shown that these bioactive peptides could be exploited for management of hypertension which is a major risk factor for cardiovascular diseases (CVDs). Antihypertensive peptides are bioactive peptides derived from plant and animal sources with inherent potential to ameliorate hypertension by different mechanism including scavenging of free radicals, reduced cholesterol level, inhibit angiotensin-converting enzyme (ACE) activity and renin production. Although there was sufficient information on ACE-inhibitory and antioxidative peptides while information on the potential role of renin-inhibitory peptides against hypertension is limited. Thus, herein the present review primarily used ISI, SCOPUS and PubMed indexed journals containing experimental reports to elucidate the potential role of bioactive peptides against antihypertensive effect via renin inhibition.
 
 Key words: Hypertension; Bioactive peptides; Renin inhibition; Mechanism of action.

Beneficial role of D allele in controlling ACE levels: a study among Brahmins of north India.

India being a country with vast diversity is expected to have different dietary and life style patterns which in turn may lead to population-specific environmental risk factors. Further, the interaction of these risk factors with the genetic makeup of population makes it either susceptible or resistant to cardiovascular disease. One such candidate gene is angiotensin converting enzyme (ACE) for various cardiovascular mechanisms. ACE is the key enzyme of the renin angiotensin aldosterone system pathway which maintains homeostasis blood pressure in the body and any variation in the levels is reported to be associated with various complex diseases. The DD genotype is found to increase ACE levels, which is associated with cardiovascular diseases and decrease in ACE levels are associated with kidney diseases. The aim of this study was to understand the distribution of ACE I/D polymorphism and ACE levels among Brahmins of National Capital Region (NCR) north India, with respect to age and sex ratio distribution. In this study, 136 subjects of which 50 males and 86 females, who were unrelated up to first cousin, aged 25 to70 years were studied. ACE gene was found to be polymorphic with high frequency of heterozygote (ID) followed by II and DD genotypes. The studied population was found to be in Hardy-Weinberg equilibrium with respect to ACE I/D polymorphism (P = 0.55). I allele frequency was found to be higher (0.560) than the D allele (0.44). The median level of ACE was found to be 65.96 ng/mL (48.12-86.24) which is towards lower side of the normal range. ACE levels were found to be increased among individual having either of the homozygotes that is II or DD and higher frequency of heterozygote (ID) is indicative of advantage in the population by maintaining lower ACE levels. The limitation of the present study is low sample size, however, the merit is that the subjects belonged to a Mendalian population with a common gene pool.

Promising New Therapies in Heart Failure: Ivabradine and the Neprilysin Inhibitors

Current guideline-directed medical therapy for heart failure (HF) is a triumph of translation medicine. An understanding of neurohormonal activation, translated into medications to block these maladaptive systems, has culminated in improved quality of life and survival for patients with HF. The most effective drug therapies for chronic systolic HF are those that inhibit the activity of the sympathetic nervous system (SNS) and renin angiotensin aldosterone system (RAAS). These agents include the beta-blockers to inhibit SNS activity and the angiotensinconverting enzyme inhibitors (Aces), angiotensin II type 1 receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRA) to act on the RAAS pathway. Two new HF medications have recently been approved and represent a deepened understanding of neurohormonal mechanisms in HF. The first is ivabradine, which inhibits the funny current of the sinoatrial node and lowers heart rate without reducing contractility. In patients already on maximally tolerated beta-blocker dosages, ivabradine reduces the risk of HF hospitalization. The second medication is sacubitril combined with valsartan, which takes advantage of the natriuretic peptide system and other endogenous vasoactive peptides. Sacubitril, a neprilysin inhibitor, increases vasoactive peptide levels resulting in beneficial effects in HF. The angiotensin receptorneprilysin inhibitor combination sacubitril/valsartan is superior enalapril in reducing death and HF hospitalizations. This review article provides an overview of guideline-directed medical therapy in HF. It highlights the mechanisms of these two new HF agents and their pivotal clinical trials and offers practical advice for prescribing these medications to HF patients.

Angiotensinogen gene polymorphisms and progression of chronic kidney disease in ADPKD patients.

Autosomal dominant polycystic kidney disease (ADPKD) is a multisystemic and progressive disorder characterized by cyst formation and kidney enlargement and ultimately renal failure. Reduction of CKD progression in the ADPKD by pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) using ACE inhibitors indicated the involvement of RAAS pathway in the progression of CKD. The aim of the present study is to investigate the role of angiotensinogen tag-single nucleotide polymorphisms (AGT tag-SNPs) in progression of CKD. Twelve AGT tag-SNPs were genotyped in 102 ADPKD patients and 106 non-ADPKD subjects using FRET-based KASPar method. Genotypes and haplotypes were compared between ADPKD and controls. The effect of genotypes and hypertension on CKD progression was assessed using univariate and multivariate logistic regression. Mantel-Haenszel (M-H) stratified analysis was performed to study the interaction between CKD stages and hypertension. Of the twelve tag-SNPs analyzed, only rs11122578 SNP deviated Hardy-Weinberg equilibrium in controls. Significant association between two AGT polymorphisms (rs11122577 and rs4762) and ADPKD was observed. Analysis of linkage disequilibrium revealed two haplotype blocksand haplotypes are not associated with ADPKD. The univariate analysis revealed that the age, hypertension, family history of diabetes and AGT rs4762 contributed to the progression of CKD in ADPKD. The modifier effect of these factors remained even after controlling other variables in multivariate analysis. The results of our study suggest significant association between Thr207Met polymorphism of AGT and CKD progression and acts as an effect modifier of renal disease progression in ADPKD.

Abstract 01: The Role of Renin-Angiotensin-Aldosterone System Genes in the Progression of Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study

Background: We conducted single-marker, gene-based and pathway-based analyses to examine the association between renin-angiotensin-aldosterone system (RAAS) variants and chronic kidney disease (CKD) progression among Chronic Renal Insufficiency Cohort (CRIC) study participants. Methods: A total of 1,523 white and 1,490 black subjects were genotyped for 490 SNPs in 12 RAAS genes as part of the ITMAT-Broad-CARe array. CKD progression phenotypes included decline in estimated glomerular filtration rate (eGFR) over time and the occurrence of a renal disease event, defined as incident end stage renal disease or halving of eGFR from baseline. Mixed-effects models were used to examine SNP associations with eGFR decline, while Cox proportional hazards models tested SNP associations with renal events. Gene and pathway-based analyses were conducted using the truncated product method. All analyses were stratified by race, and a Bonferroni correction was applied to adjust for multiple testing. Results: Among white and black participants, eGFR declined an average of 1.2 and 2.3 ml/min/1.73m 2 per year, respectively, while renal events occurred in a respective 11.5% and 24.9% of participants. We identified strong gene and pathway-based associations with CKD progression. The AGT and RENBP genes were consistently associated with risk of renal events in separate analyses of white and black participants (all P <1.00х10 -6 ). Driven by the significant gene-based findings, the entire RAAS pathway was also associated with renal events in both groups (both P <1.00х10 -6 ). No single-marker associations with CKD progression were observed. Conclusions: The current study provides strong evidence for a role of the RAAS in CKD progression.

Genetic Variations in Renin-Angiotensin-Aldosterone System (RAAS) Genes Could Contribute to High Altitude Pulmonary Edema: Review

Background: At High Altitude (HA) (elevation >2500m), inevitable hypobaric hypoxia leads to development of symptoms associated with low oxygen pressure in many non acclimatized sojourners which includes severe forms of altitude mountain sickness (AMS) such as high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). These syndromes are reportedly less common in high altitude native population than in lowlanders which can be attributed to genetic adaptations that have taken place over generations. Methods: Numerous genetic studies have been associated with hypoxic adaptation and susceptibility to high altitude conditions. An increased pulmonary arterial pressure (PAP) and fluid loss has been observed in all forms of AMS with varied intensity. Since renin-angiotensin-aldosterone system (RAAS) has a critical function of maintaining homeostasis in closed circulatory system, the polymorphisms occurring in the genes of RAAS pathway could likely be contributing towards acclimatization/mal-adaptation to high altitude maladies. In view of above, this review has been compiled to associate the genetic variations in RAAS with adaptation/acclimatization to high altitude conditions. Results: Studies conducted so far relate allele frequencies of polymorphic loci in genes encoding components of RAAS pathway such as angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin receptors (AT1) and aldosterone synthase (CYP11B2) and associate them with hypertension, regulation of blood pressure and maintenance of osmotic balance in the body. Conclusions: In this review, various studies have been put together comprehensively indicating the involvement of genetic variants of RAAS genes in resistance or sensitivity of an individual towards development of HAPE.

Renin blockade: a double-edged sword?

Aliskiren, a direct renin inhibitor, blocks the first step of the renin–angiotensin–aldosterone system (RAAS), thereby reducing plasma renin activity and the circulating levels of angiotensin I, angiotensin II, and aldosterone. Extensive RAAS blockade can be achieved through the administration of aliskiren; however, renin blockade is a double-edged sword because the renin/prorenin receptor-associated pathway is also reportedly modulated by direct renin inhibitor. This research highlight discusses the findings of a recent clinical study of aliskiren and explores the complex interactions of key molecules in the RAAS pathway in response to aliskiren administration.

Clinical utility of valsartan in treatment of children and adolescents with high blood pressure

The incidence of hypertension in the pediatric population has been increasing secondary to lifestyle changes in children and adolescents. Recent studies have enhanced our understanding of the treatment of pediatric hypertension. Angiotensin-converting enzyme inhibitors have traditionally been the most commonly used class of medication in children with hypertension. This is partly due to the important role of the renin angiotensin aldosterone system pathway in the mediation of pediatric hypertension. Angiotensin receptor blockers provide a reasonable alternative to angiotensin-converting enzyme inhibitors. The need for better tolerated antihypertensives had led to development of many new antihypertensives. Valsartan is a relatively novel angiotensin receptor blocker that has been shown to be effective in the treatment of pediatric hypertension. Two recent trials have demonstrated the efficacy of valsartan monotherapy in the pediatric population aged 1–16 years. Once-daily oral preparations of valsartan achieve adequate blood pressure control in the pediatric population. Lack of generic formulations is an important disadvantage. Plasma levels are predictable and clearance is primarily by the liver. Valsartan should be prescribed cautiously for sexually active adolescent females due to concern about angiotensin receptor blocker fetopathy. Otherwise, the drug has infrequent side effects. In summary, valsartan is a new and useful alternative to conventional antihypertensive therapy in pediatric population.

Chronic renal insufficiency among Asian Indians with type 2 diabetes: I. Role of RAAS gene polymorphisms

BackgroundRenal failure in diabetes is mediated by multiple pathways. Experimental and clinical evidences suggest that renin-angiotensin-aldosterone system (RAAS) has a crucial role in diabetic kidney disease. A relationship between the RAAS genotypes and chronic renal insufficiency (CRI) among type 2 diabetes subjects has therefore been speculated. We investigated the contribution of selected RAAS gene polymorphisms to CRI among type 2 diabetic Asian Indian subjects.MethodsTwelve single nucleotide polymorphisms (SNPs) from six genes namely-renin (REN), angiotensinogen (ATG), angiotensin converting enzyme I (ACE), angiotensin II type 1 receptor (AT1) and aldosterone synthase (CYP11B2) gene from the RAAS pathway and one from chymase pathway were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and tested for their association with diabetic CRI using a case-control approach. Successive cases presenting to study centres with type 2 diabetes of ≥2 years duration and moderate CRI diagnosed by serum creatinine ≥3 mg/dl after exclusion of non-diabetic causes of CRI (n = 196) were compared with diabetes subjects with no evidence of renal disease (n = 225). Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair wise interactions between SNPs of different genes.ResultsOf the 12 SNPs genotyped, Glu53Stop in AGT and A>T (-777) in AT1 genes, were monomorphic and not included for further analysis. We observed a highly significant association of Met235Thr SNP in angiotensinogen gene with CRI (O.R. 2.68, 95%CI: 2.01–3.57 for Thr allele, O.R. 2.94, 95%CI: 1.88–4.59 for Thr/Thr genotype and O.R. 2.68, 95%CI: 1.97–3.64 for ACC haplotype). A significant allelic and genotypic association of T>C (-344) SNP in aldosterone synthase gene (O.R. 1.57, 95%CI: 1.16–2.14 and O.R. 1.81, 95%CI: 1.21–2.71 respectively), and genotypic association of GA genotype of G>A (-1903) in chymase gene (O.R. 2.06, 95%CI: 1.34–3.17) were also observed.ConclusionSNPs Met235Thr in angiotensinogen, T>C (-344) in aldosterone synthase, and G>A (-1903) in chymase genes are significantly associated with diabetic chronic renal insufficiency in Indian patients and warrant replication in larger sample sets. Use of such markers for prediction of susceptibility to diabetes specific renal disease in the ethnically Indian population appears promising.

Non-accidental dettol poisoning in a 3 day old neonate : a rare form of child abuse

Background : The incidence of hypertension in the pediatric population has been increasing. Childhood blood pressure is predictive of adult BP. The renin angiotensin aldosterone system pathway is important in the mediation of pediatric hypertension. New therapies approved for adults are often used off label in children with little or no efficacy and safety data in the paediatric population The angiotensin receptor blockers has been shown to be effective and safe in the treatment of pediatric hypertension. Objective : The objective of this review is to highlight available clinical evidence on the efficacy, safety tolerability and kinetics of angiotensin receptor blockers in childhood hypertension and its antiproteinuric effect in renal disease. Method : The search strategy was based on Pubmed, Medline database, Cochrane Library, manual, Google and Yahoo searches. We summarized ten randomized controlled trials (RCTs) .The search was done in June 2014 and updated in January and May 2015 in English language . Results : A total of 120 publications were accessed from which 68 references were included in the review. The design and outcome of ten key randomised trials are summarised. Randomised trials have demonstrated the efficacy of angiotensin receptor blockers in the pediatric population aged 1–16 years. This class of drugs reduce blood pressures in pediatric patients with hypertension and proteinuria in renal disease. Safety pharmacokinetic, dosage, and palatability of adult formulations for the paediatric age group are highlighted Conclusion : Angiotensin receptor antagonists are useful effective and safe alternatives to available antihypertensive therapy in paediatric population. Angiotensin receptor antagonists should however be prescribed cautiously for sexually active adolescent females due to concern about angiotensin receptor blocker fetopathy. Keywords : Angiotensin receptor blockers, childhood hypertension, drug safety, drug efficacy, pharmacokinetics and renal diseases.

Use of angiotensin II receptor blockers in children- a review of evidence

Background: The incidence of hypertension in the pediatric population has been increasing. Childhood blood pressure is predictive of adult BP. The renin angiotensin aldosterone system pathway is important in the mediation of pediatric hypertension. New therapies approved for adults are often used off label in children with little or no efficacy and safety data in the paediatric population The angiotensin receptor blockers has been shown to be effective and safe in the treatment of pediatric hypertension.Objective: The objective of this review is to highlight available clinical evidence on the efficacy, safety tolerability and kinetics of angiotensin receptor blockers in childhood hypertension and its antiproteinuric effect in renal disease.Method: The search strategy was based on Pubmed, Medline database, Cochrane Library, manual, Google and Yahoo searches. We summarized ten randomized controlled trials (RCTs) .The search was done in June 2014 and updated in January and May 2015 in English language .Results: A total of 120 publications were accessed from which 68 references were included in the review. The design and outcome of ten key randomised trials are summarised. Randomised trials have demonstrated the efficacy of angiotensin receptor blockers in the pediatric population aged 1–16 years. This class of drugs reduce blood pressures in pediatric patients with hypertension and proteinuria in renal disease. Safety pharmacokinetic, dosage, and palatability of adult formulations for the paediatric age group are highlightedConclusion: Angiotensin receptor antagonists are useful effective and safe alternatives to available antihypertensive therapy in paediatric population. Angiotensin receptor antagonists should however be prescribed cautiously for sexually active adolescent females due to concern about angiotensin receptor blocker fetopathy.Keywords: Angiotensin receptor blockers, childhood hypertension, drug safety, drug efficacy, pharmacokinetics and renal diseases.