Angiotensin System Genes Research Articles

Mineralocorticoid and glucocorticoid receptors in sciatic nerve function and regeneration

The contribution of the two corticosteroid (mineralocorticoid and glucocorticoid) receptor (MR and GR) pathways to the function and regeneration of the sciatic nerve was investigated. We found that the corticosterone-inactivating enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD2) was up-regulated 7 days after lesion in freeze-injured nerve. The maintenance of a low intracellular level of corticosterone by HSD2 activity in the regenerating nerve is concordant with the improvement of nervous function in injured animals (as measured by walking ability) after treatment by the GR antagonist mifepristone and with the reduction in GR participation in accumulation of the mRNA for numerous endogenous genes (from the renin–angiotensin system and other classical mineralocorticoid-responsive genes), in the same animals. Furthermore, using the MR antagonist spironolactone, we demonstrated that MR plays an active role in the function of the intact sciatic nerve: MR is required for walking ability and participates in the control of the accumulation of the mRNA for several endogenous genes. However, after injury, changes in gene expression cannot be fully explained by changes in MR/GR activity, due to an HSD2 effect, and other signalling pathway(s) induced by the lesion likely combine with the effect of the corticosteroid receptors.

Renin Angiotensin System Gene Polymorphisms Modify Angiotensin‐Converting Enzyme Inhibitors' Effect on Cognitive Function: The Health, Aging and Body Composition Study

To investigate the effect of polymorphisms in renin angiotensin system genes on the association between angiotensin-converting enzyme inhibitor (ACEI) exposure and global and executive cognitive function in the Health, Aging and Body Composition study. Cohort study. Community. Three thousand seventy-five participants: mean age 73.6, 58% Caucasian, 52% female, 15% taking ACE-Is, 8 years of follow-up. The outcomes were longitudinal change in Executive Clock Drawing Test-1 (CLOX1), the Digit Symbol Substitution test, and the Modified Mini-Mental State Examination. The genetic polymorphisms included angiotensin-converting enzyme insertion deletion (ACEID) in the ACE gene and the M235T and 6AG polymorphisms in the angiotensinogen (AGT) gene. For the CLOX1 outcome, there was significant interaction between 6AG and M235T polymorphisms in the AGT gene and angiotensin-converting enzyme inhibitors (ACE-Is) in Caucasian participants (P=.01 for both polymorphisms) independent of blood pressure levels. Specifically, ACE-I exposure was protective against CLOX1 score decline in carriers of the AA genotype of the 6AG and the CC genotype of the M235T (for the ACE-I vs non-ACE-I groups, P=.01 for 6AG and P=.005 for M235T) but not the other genotypes. These associations were not significant with other cognitive tests, with ACEID, or in African Americans. ACE-Is may provide a protective effect on executive function in Caucasians with AGT gene polymorphisms known to be associated with greater renin angiotensin system activity. If confirmed in a pharmacogenetic trial, ACE-Is may be found to have additional cognitive protection in a select group of elderly individuals.

Genotypic interactions of renin–angiotensin system genes with diabetes type 2 in a Tunisian population

Aims To explore the role of genetic variants of angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE I/D), and angiotensin type 1 receptor (AT1R A1166C) as predictors of diabetes risk and to examine their combined effects on type 2 diabetes mellitus (T2DM) patients. Main methods One hundred and fourteen T2DM patients were compared to 175 healthy controls with similar age and sex. Key findings The genotypic frequencies for all three genes alone were significantly associated with increased risk of developing diabetes. Logistic regression analysis of classic coronary risk factors and the genetic polymorphisms demonstrated that hypertension and ACE DD genotype were the most significant contributors to T2DM. For the renin–angiotensin system (RAS) genes, the risk of T2DM in individuals with one risk genotype was 1.9 (95%CI: 1.1–3.0, p = 0.017) higher than those with zero risk genotype. Individuals who carried two risk genotypes had a 4.0 (95%CI 1.7–9.4, p = 0.001) times higher risk of T2DM than those who did not carry any risk genotypes of the RAS genes. Most interestingly, the risk of T2DM for individuals with three risk genotypes was 26.2 (95%CI: 5.8–117.9, p < 0.001) higher than those with zero risk genotype. Significance The results of the present study imply that genotyping of renin–angiotensin system genes could become an important part of the clinical process of risk identification for T2DM in Tunisian population.

141. METHYLATION OF GENES OF THE RENIN ANGIOTENSIN SYSTEM (RAS) IN EARLY HUMAN AMNION

The renin angiotensin system (RAS) genes angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1) and prorenin receptor (ATP6AP2) have CpG islands at their promoters, so these genes may be regulated by CpG island methylation as may the expression of two proteases implicated in prorenin activation (cathepsin D {CTSD} and kallikrein 1 {KLK1}). We measured CpG island methylation of 3 RAS genes and of CTSD and KLK1 in amnion using the Methyl-Profiler assay (SA Biosciences), which discriminates methyl-CpG density between hypermethylated, intermediately methylated and unmethylated CpG islands. DNA from human amnion collected between 10–17.8 weeks gestation, at elective caesarean section and after labour at term was analysed. The bulk (&gt;80%) of CpG islands in all genes examined except for KLK1 was unmethylated and without intermediate methylation throughout gestation, while the rest was hypermethylated. There was no change in methylation density with labour (Table 1). In early gestation KLK1 methylation was greater than ACE, AGTR1 and ATP6AP2 (P &lt; 0.05). KLKI methylation shifted towards the unmethylated state after labour (P &lt; 0.05). There were correlations between methylation of ACE, AGTR1 and ATP6AP2 (P &lt; 0.02) but not between RAS genes and KLKI. This suggests that the 3 RAS genes in amnion are not controlled by CpG island methylation. It is likely, however, that KLK1 is silenced in early gestation amnion partially by CpG island methylation, which is reduced by term. Since Kallikrein 1 can activate prorenin, the methylation status of this gene may regulate RAS activity in amnion during gestation.

Imaging and genetics advances in understanding geriatric depression

Over a decade has passed since publication of the vascular depression hypothesis that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes (Alexopoulos et al, 1997). This construct has catalyzed much research, largely focused on structural neuroimaging, clinical neuropsychology, and in last few years, genetics and cognitive neuroscience. Recent investigations have combined advanced neuroimaging techniques and genetic analyses to delineate key structural and functional findings in late-life depression (LLD). Vascular brain changes on imaging studies have long been associated with LLD. Genetic analysis of vascular changes is an emerging field, and recent work in older populations has focused on polymorphisms associated with (1) psychiatric disease in younger adults or (2) vascular risk factors. We have previously reported links between BDNF (brain-derived neurotrophic factor) polymorphisms (Taylor et al, 2008) and serotonin transporter-linked polymorphic region (5HTTLPR) polymorphisms (Steffens et al, 2008) and white matter hyperintensity (WMH) volumes, supporting theories that these genes also have a role in LLD. The notion that WMHs are vascular in nature led our group to explore relationships between WMH volume and genes associated with systemic vascular risk. These include renin–angiotensin system genes, such as the angiotensin II receptor, vascular types 1 and 2 (AGTR1 and AGTR2) genes. In addition to reports linking AGTR1 polymorphisms to LLD outcomes, we have also found gender-specific associations between AGTR polymorphisms and WMH progression (Taylor et al, 2009). Similarly, the methylenetetrahydrofolate reductase (MTHFR) gene, another vascular risk gene associated with folate and homocysteine metabolism, may be associated with LLD, and we are examining MTHFR and other genes related to folate metabolism in the occurrence of white matter lesions in LLD. Our studies continue to examine the role of vascular risk genes in LLD, focusing on their influence on brain structure and cognition. Consistent with the vascular depression hypothesis is the notion the LLD is associated with disruption in frontal-striatal circuitry. These abnormalities in the prefrontal cortex, striatum, and frontal-striatal white matter tracks are also likely related to genetic differences. A previous study noted a link between the 5HTTLPR short allele and caudate volume in LLD. We recently reported an interaction between two genes, COMT (catechol-O-methyltransferase) and MTHFR, and putamen volume reduction in LLD (Pan et al, 2009). Identification of genes associated with prefrontal cortical structure and function remains an active area of inquiry. Beyond the vascular depression hypothesis, another avenue of genetic/neuroimaging LLD research examines the observed link between depression and later dementia. The hippocampus is a key structure related to both LLD pathophysiology and increased dementia risk. The APOE gene is associated with both depression and Alzheimer's disease, and APOE genotype has been associated with specific shape differences in geriatric depression (Qiu et al, 2009). Allelic differences in the 5HTTLPR gene have also been associated with hippocampal volume in LLD by several groups. Advances in both neuroimaging technologies and genetic assessment allow us to investigate the pathophysiology of affective disorders. Existing paradigms of vascular depression and depression as dementia risk make LLD ideally suited for future genetic/imaging studies.

Analysis of polymorphism in Renin Angiotensin System and other related genes in South Indian chronic kidney disease patients

Background Several Renin Angiotensin System (RAS) polymorphisms alter the homeostasis to an abnormal state. Similarly, other genes such as Nephrin (NPHS1) and Podocin (NPHS2) contribute to the loss of renal function during renal diseases. In Indian population, studies in RAS and other renal specific gene polymorphisms in Chronic Kidney Disease (CKD) patients are scanty. Methods We examined 118 CKD patients and 98 control subjects for the occurrence of common polymorphisms in angiotensin converting enzyme insertion/deletion ( ACE; I/D), angiotensinogen ( AGT; M235T), chymase ( CMA; − 1903G > A), angiotensin receptor type-1 ( AGTR1-1166A > C), methylene tetrahydrofolate reductase ( MTHFR; 677C > T), nephrin ( NPHS1; R1160X) and podocin ( NPHS2; R291W and R229Q). Result Significant association was observed in AGT-M235T polymorphism between CKD patients and controls. The frequency of TT genotype was higher in CKD patients when compared with controls (0.39 vs. 0.14; χ 2 = 20.3, P < 0.001). ACE- DD genotype showed a higher level of systolic pressure with a median of 166 mmHg ( P < 0.05) when compared to II and ID genotypes. Two heterozygous conditions of NPHS2-R229Q polymorphism were found among 105 CKD patients. No significant associations were found in genotype frequencies in other above polymorphisms between CKD patients and controls. Conclusion Asian Indian population with AGT-TT genotypes may have a higher relative risk towards CKD with odds ratio (OR) 3.98 (95% CI = 1.92–8.25; P = 0.0002).

Core Promoter Variants (A-20C, T-18C and G-6A) of the Angiotensinogen (AGT) Gene are not Significantly Associated with Hypertension in Patients of Tamilnadu, India

Hypertension is a complex multifactorial disease, which affects 10-30 % of the world population. The genetic factors of the hypertension vary from population to population. Renin angiotensin system (RAS) genes play a key role in salt-water homeostasis and blood pressure regulation. The genetic polymorphisms of the angiotensinogen (AGT) gene are associated with hypertension in different populations and some of these polymorphisms (G-6A and M235T) have a significant role in the human evolution and selection fitness. The present study was carried out to find out the role of the core promoter variants {-20(A-20C),-18(T-18C) and -6(G-6A)} in causing hypertension in rural and urban hypertensive patients of Tamilnadu. Methods: A total of 254 hypertensive and 254 normotensive subjects were screened using PCR-SSCP and RFLP methods followed by DNA sequencing. The sequences were analysed by BLAST. Results: The genotype frequencies of A-20C (AA,AC,CC), C-18T (CC,CT, TT) and -6G(AA,AG,GG) in patients/controls respectively were 63.0,33.0,4.0/67.5,28.5,4.0; 99.0,1.0,0.0/99.6,0.4,0.0 and 83.0,17.0,0.0/ 81.6,18.5,0.0 Observation and Conclusion: None of these promoter variants were significantly associated with hypertension. The A allele of G-6A polymorphism was found in a high frequency in patients and controls (about 91%) which correlates with frequencies observed in African and Asian ethnic populations (80-95%).

A propensity score-based case–control study of renin–angiotensin system gene polymorphisms and diastolic heart failure

Angiotensin II plays an important role in diastolic heart failure (DHF). However, genetic studies of DHF are scarce in the literature. We hypothesized that RAS genes might be the susceptible genes for DHF and conducted a propensity score-based case–control study to prove this hypothesis. A total of 666 subjects (285 diagnosed with DHF confirmed by echocardiography and 381 without diastolic dysfunction) were recruited. Genotyped were: the angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism; the T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen (AGT) gene; and the A1166C polymorphisms of the angiotensin II type I receptor (AT1R) gene. Propensity scores (PS) were used to find patients with and without DHF with equalized characteristics. We also assembled another set of PS matched groups for all characteristics except left ventricular mass (LVM) to detect the genetic association with DHF through the effect of left ventricular hypertrophy. PS matched 210 patients with DHF to 210 without. In a single-locus analysis, the odds ratios (ORs) for DHF were significant with the ACE DD genotype (OR = 1.30, 95% CI = 1.13–1.49, permuted P = 0.003) and the AT1R 1166 CC genotype (OR = 2.61, 95% CI = 1.52–4.45, permuted P < 0.001). Significant gene–gene interaction between the two genes was also detected. However, the ACE gene effect was diminished if LVM was not controlled in the propensity scores. We concluded that genetic variants in the RAS genes may determine individual risk to develop DHF through different pathways. Concomitant presence of ACE DD and AT1R 1166 CC genotypes synergistically increased the predisposition to DHF.

Renin–Angiotensin System and α-Adducin Gene Polymorphisms and Their Relation to Responses to Antihypertensive Drugs: Results From the GENRES Study

Polymorphisms in genes coding for components of the renin-angiotensin system (RAS) and alpha-adducin (ADD1) have been reported to be associated with blood pressure (BP) responses to antihypertensive agents. The results, however, have not been consistent and most of the earlier studies have been small and lacked placebo-control. Therefore, the association of common polymorphisms in these genes with BP responses to four different antihypertensive drugs was analyzed in a controlled study. The study included 208 hypertensive Finnish men from the GENRES study. All of them used amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide (HCT) 25 mg, and losartan 50 mg daily, each for 4 weeks as a monotherapy in a double-blind, randomized, study. The treatment periods were separated by 4-week placebo periods. Both 24-h ambulatory (ABP) and office BP (OBP) measurements were carried out. The polymorphisms analyzed were ADD1 Gly460Trp, angiotensinogen (AGT) Met235Thr, angiotensin converting enzyme (ACE) insertion/deletion (I/D), and angiotensin II type 1 receptor (AGTR1) 1166A/C. The presence of 460Trp allele of ADD1, previously suggested to be a marker of thiazide responsiveness, did not predict a better response to HCT. There was no significant association of AGT Met235Thr, ACE I/D, and AGTR1 1166A/C polymorphisms with BP responses to the study drugs. ADD1 460Trp and AGT 235Thr alleles were associated with higher systolic white coat effect (WCE) during the placebo periods (P values 0.03 and 0.01, respectively). Common polymorphisms of ADD1, AGT, ACE, and AGTR1 do not markedly predict BP responses to amlodipine, bisoprolol, HCT, and losartan, at least in white hypertensive men.

Association between renin–angiotensin system gene polymorphism and essential hypertension: a community-based study

Renin-angiotensin (RAS) genes, a group of promising candidate genes involved in essential hypertension (EH), play a key role in blood pressure regulation. Recently, a series of novel RAS gene polymorphisms were reported, which significantly influence the rate of the gene transcription. This study was designed to explore the association between the RAS gene polymorphisms and EH in a remote countryside population. We examined six polymorphisms in the main component genes of RAS: angiotensin-converting enzyme (ACE) (I/D), angiotensinogen (AGT) (A-6G, A-20C, G-217A and T174 M) and angiotensin type 1 receptor (AT1R) (A1166C). Six polymorphisms were genotyped by gene chip technology. Association studies were performed in 220 EH patients and 235 normotensives. Our results revealed that AGT A-6G, T174 M and ACE-I/D were significantly associated with EH (AGT A-6G: AG+GG vs AA; OR=1.36; 95% CI=1.04-1.77. T174M: CT+TT vs CC; OR=1.45; 95% CI=1.15-1.90. ACE I/D: ID+DD vs II; OR=1.171; 95% CI=1.00-1.37). Moreover the logistic regression analysis suggested that the haplotype of AGT -6A, 174C, -217G and -20A might decrease the risk of EH (OR=0.64; 95% CI=0.49-0.83), after adjusting the confounding factors of gender, age and BMI. In conclusion, the AGT A-6G, T174 M and ACE I/D polymorphisms are associated with EH and the AGT haplotype -6A, 174C, -217G and -20A decrease the risk of EH in the southern Chinese population.

Renin–angiotensin System Genes and Coronary Artery Calcification

Evaluation of: Kretowski A, McFann K, Hokanson JE et al.: Polymorphisms of the renin-angiotensin system genes predict progression of subclinical coronary atherosclerosis. Diabetes 56, 863-871 (2007). The mechanisms giving rise to the increased risk of coronary artery disease (CAD) in patients with Type 1 diabetes compared with the general population are still incompletely understood. In the study considered here, coronary artery calcification (CAC), a marker of subclinical CAD, was measured over a mean 2.5-year period in approximately 500 subjects with Type 1 diabetes and 500 controls. Polymorphisms in the renin-angiotensin system genes were found to be predictive of CAC progression in diabetic subjects, but only in the absence of treatment with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. This association could help in understanding the development of CAD in diabetic patients. However, because of the dangers of overinterpreting subgroup analyses and multiple testing, the findings require replication in a confirmatory study.

AGT and ACE genes influence classic mitral valve prolapse predisposition in Marfan patients

Background In Marfan syndrome, the mitral valve prolapse, ranging from nonclassic to classic form on the basis of the leaflet thickness, is a common condition characterized by a highly variable structural abnormality. We investigated the role of angiotensinogen ( AGT) M235T, angiotensin converting enzyme ( ACE) I/D and angiotensin II type 1 receptor ( AT1R) A1166C polymorphisms in influencing the susceptibility to classic or non-classic mitral valve prolapse in Marfan patients. Methods We studied 135 Marfan patients with mitral valve prolapse, diagnosed by echocardiography. AGT, ACE, and AT1R polymorphisms were identified by polymerase chain reaction-based restriction analysis. Results The frequency of the ACE D, but not AGT 235T and AT1R 1166C allele, was significantly higher in patients with classic mitral valve prolapse in comparison to that observed in the non-classic one ( p = 0.03). The percentage of subjects with the contemporaneous presence of ACE D and AGT 235T alleles was significantly higher in the classic mitral valve prolapse group in comparison to the non-classic one (79% vs. 55%, respectively; p = 0.008). The concomitant presence of these two alleles was associated with increased susceptibility to the classic mitral valve prolapse ( OR 3.02, p = 0.016). Conclusions Our findings show a possible role of ACE and AGT genes as predisposing factors to classic mitral valve prolapse in Marfan patients, thus suggesting a role of renin angiotensin system genes in modulating mitral valve abnormality, and the need for an interventional study with angiotensin II type 1 receptor antagonists, which considers the leaflet thickness progression in Marfan patients with MVP.

Sucrose overload during pregnancy and lactation influences blood pressure, body weight, and renin angiotensin system gene expression in adult offspring.

Sucrose overload during pregnancy and lactation influences blood pressure, body weight, and renin angiotensin system gene expression in adult offspring.

Renin–angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: Detection of high order gene–gene interaction

There have been many reports regarding the association between renin–angiotensin system (RAS) gene polymorphisms and coronary artery disease (CAD) or acute myocardial infarction (AMI), but the results are inconsistent. In the present study, we used several new approaches with multilocus data to reappraise this issue in a large and relatively homogeneous Taiwanese population. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with documented coronary artery disease and 519 without) between 1996 and 2003 were recruited. Angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen gene; and A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In single-locus analyses, no locus was associated with CAD, history of AMI and three-vessel CAD, either with or without adjustment for conventional CAD risk factors. For multilocus analyses, we recreated a balanced population, with the controls individually matched to the cases regarding the conventional CAD risk factors. We found that the angiotensinogen gene haplotype profile was significantly different between the cases and controls ( χ 2 = 31.6, P = 0.030) in haplotype analyses. Furthermore, significant three-locus (G-217A, M235T and I/D) gene–gene interactions were detected by multifactor-dimensionality reduction method (highest cross-validation consistency 10.0, lowest prediction error 40.56%, P = 0.017) and many even higher order gene–gene interactions by multilocus genotype disequilibrium tests (16 genotype disequilibria exclusively found in the controls, all of which included at least two genes among AGT, ACE and AT1R genes). Our study is the first to demonstrate epistatic, high-order, gene–gene interactions between RAS gene polymorphisms and CAD. These results are compatible with the concept of multilocus and multi-gene effects in complex diseases that would be missed with conventional approaches.

Influence of Salt Intake on Renin–Angiotensin and Natriuretic Peptide System Genes in Human Adipose Tissue

We tested the hypothesis that changes in sodium intake modulate adipose-tissue renin-angiotensin and natriuretic peptide system gene expression in humans. We studied 9 healthy young men in a metabolic ward at constant room temperature, humidity, and water, potassium, and calcium intake. Subjects were submitted to 4 different periods of sodium intake, and blood samples, microdialysis samples (interstitial fluid), and biopsies from subcutaneous abdominal adipose tissue were obtained at the end of the low-sodium period (0.7 mmol Na/kg per day) and at the end of the high-sodium period (7.7 mmol Na/kg per day). Urinary sodium excretion was 64+/-4 mmol per day with the low-sodium diet and 521+/-8 mmol per day with the high-sodium diet. Systemic and microdialysate sodium concentrations were similar with both interventions. With high-sodium intake, systemic renin activity and aldosterone levels were suppressed, angiotensin-converting enzyme activity did not change, and systemic levels of the atrial natriuretic peptide increased. High-sodium diet increased angiotensin-converting enzyme and atrial natriuretic peptide gene expression in adipose tissue. None of the other genes tested were influenced by changes in dietary sodium intake. Our findings suggest that the adipose-tissue renin-angiotensin system is not part of a feedback mechanism regulating sodium homeostasis and blood pressure. Systemic and adipose-tissue renin-angiotensin systems are regulated at least in part independently from each other. In contrast, systemic atrial natriuretic peptide and adipose-tissue atrial natriuretic peptide respond similarly to changes in sodium intake.

Renin–angiotensin system gene polymorphisms: association with susceptibility to Henoch–Schonlein purpura and renal involvement

The clinical course of Henoch-Schönlein Purpura (HSP) in children is variable, with some patients having a much more rapidly progressing course than others. We investigated whether polymorphisms of the renin-angiotensin system (RAS) genes are involved in HSP. Three RAS genotypes were examined in 114 children with HSP and in 164 healthy children: the angiotensin I converting enzyme (ACE) insertion/deletion polymorphism, the M235T mutation in the angiotensinogen gene (Agt), and the A1166C in the angiotensin II type I receptor (AT1R) gene. Significant differences were observed between HSP patients and control group in the frequency of ACE and Agt genotypes (p=0.004 and p=0.003, respectively). The TT genotype of Agt gene was associated with a 3.5-fold increased risk for Henoch-Schönlein nephritis (HSN) compared with the MM/MT genotype (odds ratio, 3.5; 95% confidence interval, 1.2-10.4). There was a trend to a higher prevalence of the TT genotype of the Agt gene among patients with nephrotic range proteinuria when compared to the patients with mild proteinuria, although the difference did not reach a statistical significance. The results of this study suggest that polymorphisms of ACE gene and Agt gene likely influence the risk of developing HSP. However, among the three genes of the RAS studies, only Agt gene was associated with the susceptibility to HSN. RAS gene polymorphisms studied are not associated with the presence of nephrotic range proteinuria. Additional studies are warranted to verify the correlation between RAS gene polymorphisms and susceptibility to HSP.

Altered renin–angiotensin system gene expression causes renal hypoplasia in the rats with nitrofen-induced diaphragmatic hernia

The association between renal hypoplasia and pulmonary hypoplasia in congenital diaphragmatic hernia (CDH) has become recently appreciated. However, the underlying mechanisms responsible for this association are still unknown. Renin-angiotensin system (RAS) plays an important role in renal and somatic growth, angiogenesis and reproduction. We hypothesized that abnormal expression of RAS components may be responsible for renal hypoplasia in CDH. We therefore designed this study to examine the gene expression of main components of RAS in the kidney of nitrofen-induced CDH in the rat. Pregnant rats were exposed to either olive oil or 100 mg of nitrofen on day 9.5 of gestation. Foetuses were recovered at term and divided into three groups: control (n=8), nitrofen without CDH (n=8) and CDH (n=8). Reverse transcription polymerase chain reaction was performed to evaluate the relative amount of angiotensinogen (AGT), angiotensin II type 1 receptor with 1a and 1b subtypes (AT(1a)R and AT(1b)R), angiotensin II type 2 receptor (AT(2)R), angiotensin-converting enzyme (ACE) and renin expression in the kidney. AT(1a)R, AT(1b)R, AT(2)R, AGT and renin levels were significantly decreased in the kidney of CDH rats compared with controls. We did not find a significant difference in ACE between CDH animals and controls. Our data show that the downregulation of RAS may play an important role in the pathogenesis of renal hypoplasia in the nitrofen-induced CDH.

Association of renin–angiotensin system gene polymorphisms with antihypertensive responses to angiotensin-converting enzyme inhibition or angiotensin receptor blockade

Association of renin–angiotensin system gene polymorphisms with antihypertensive responses to angiotensin-converting enzyme inhibition or angiotensin receptor blockade

Renin–angiotensin system gene polymorphisms predict the progression to renal insufficiency among Asians with lupus nephritis

The renin-angiotensin system (RAS) is a strong candidate as a mediator for the development and progression of lupus nephritis (LN). We performed an ethnically stratified analysis of 642 systemic lupus erythematosus (SLE) patients to determine whether various functional RAS gene polymorphisms are associated with SLE renal outcomes. Patients were genotyped for two angiotensin-converting enzyme (ACE) gene polymorphisms: Alu insertion/deletion (I/D) and 23 949 (CT)(2/3), and for two angiotensinogen (Atg) gene polymorphisms: M235T and C-532T. Multivariate analyses demonstrated associations between the ACE I/D, ACE (CT)(2/3) and Atg C-532T functional polymorphisms and LN among Asians. In stratified analyses among LN cases according to high vs low glomerular filtration rate (GFR), associations remained significant for the ACE D (odds ratio (OR) 5.9, P=0.001) and (CT)(2) (OR 6.2, P=0.001) alleles among Asian subjects with low GFR. Lastly, we found allelic dose-dependent associations between the ACE I/D (P=0.003), ACE (CT)(2/3) (P=0.005) and Atg M235T (P=0.04) polymorphisms, and GFR analyzed as a continuous variable among Asians. These findings suggest a significant role for ACE and Atg gene sequence variation and severity of LN among Asians with SLE.

Angiotensin system polymorphisms and traditional risk factors as predictors of heart failure prognosis

Background Traditional risk factors affect heart failure (HF) severity and outcomes. We investigated whether angiotensin system gene polymorphisms would offer additional prognostic information when considered with traditional risk factors. Methods Patients with chronic HF were enrolled and followed for first event (all-cause mortality, heart transplant, or HF hospitalization). Logistic regression was used to examine the effects of covariates on outcome. Variables included risk factors previously shown to affect prognosis in our population as well as polymorphisms in the ACE (ACE I/D), angiotensinogen (AGT 235T/C), and angiotensin type 1 receptor (AGTR1 1166A/C) genes determined by pyrosequencing or dHPLC. β-blocker, ACE inhibitor, and diuretic use was near unity at baseline and end of follow-up and not included in the model. Significance for inclusion in the model was set at 0.1. Results Patients (n=237) were followed for a median of 18 months (6 months min, 36 months max). Significant markers of HF prognosis are presented (see Table). Polymorphisms in three genes of the angiotensin system were not associated with outcomes, nor were age, race, sex, diabetes, dyslipidemia, or serum creatinine. Conclusion Angiotensin system genes were not associated with HF prognosis in this population. The high use of ACE inhibitors and β-blockers in this population may have ameliorated genetic influence on prognosis. Clinical Pharmacology & Therapeutics (2005) 77, P63–P63; doi: 10.1016/j.clpt.2004.12.130 Table 1. Variable Odds Ratio 90 CI P-value Serum sodium 0.86 0.78–0.93 0.003 NYHA class 1.84 1.31–2.60 0.003 Previous CABG 1.85 1.03–3.30 0.08