angiotensinogen and Diabetes-Mellitus--Type-2

Hypertension remains the leading cause of cardiovascular disease and premature death globally, affecting half of US adults. A high proportion of hypertensive patients exhibit uncontrolled blood pressure (BP), associated with poor adherence, linked to pill burden and adverse effects. Novel pharmacological strategies are urgently needed to improve BP control. Dysregulation of the renin-angiotensin system increases BP through its primary effector, Ang II (angiotensin II), which results in tissue remodeling and end-organ damage. Silencing liver angiotensinogen (the sole source of Ang II) has been achieved using novel RNA therapeutics, including the antisense oligonucleotide, IONIS-AGT (angiotensinogen)-LR

Topics: Angiotensin II; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Humans; Hypertension; Renin-Angiotensin System; RNA, Small Interfering

The association of polymorphisms in the renin-angiotensin-aldosterone system candidate genes, namely Angiotensin-Converting Enzyme (ACE) Insertion/Deletion (I/D), Angiotensinogen (AGT) M235T and Angiotensin II Receptor Type 1 (AGTR1) A1166C with Diabetic Nephropathy (DN) has been studied for decades.. This meta-analysis aimed to assess the updated pooled effects of these polymorphisms with DN among Asian populations with type 2 diabetes mellitus.. The PubMed electronic database was searched without duration filter until August 2017 and the reference list of eligible studies was screened. The association of each polymorphism with DN was examined using odds ratio and its 95% confidence interval based on dominant, recessive and allele models. Subgroup analyses were conducted based on region, DN definition and DM duration.. In the main analysis, the ACE I/D (all models) and AGTR1 A1166C (dominant model) showed a significant association with DN. The main analysis of the AGT M235T polymorphism did not yield significant findings. There were significant subgroup differences and indication of significantly higher odds for DN in terms of DM duration (≥10 years) for ACE I/D (all models), AGT M235T (recessive and allele models) and AGTR1 A1166C (recessive model). Significant subgroup differences were also observed for DN definition (advanced DN group) and region (South Asia) for AGTR1 A1166C (recessive model).. In the Asian populations, ACE I/D and AGTR1 A1166C may contribute to DN susceptibility in patients with T2DM by different genetic models. However, the role of AGT M235T needs to be further evaluated.

Topics: Angiotensinogen; Asian People; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Genetic Predisposition to Disease; Humans; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Excess adiposity can induce adverse sequelae in multiple cell types and organ systems. The transition from the lean to the obese state is characterized by fundamental cellular changes at the level of the adipocyte. These changes affect the local microenvironment within the respective adipose tissue but can also affect nonadipose systems. Adipocytes within fat pads respond to chronic nutrient excess through hyperplasia or hypertrophy, which can differentially affect interorgan crosstalk between various adipose depots and other organs. This crosstalk is dependent on the unique ability of the adipocyte to coordinate metabolic adjustments throughout the body and to integrate responses to maintain metabolic homeostasis. These actions occur through the release of free fatty acids and metabolites during times of energy need - a process that is altered in the obese state. In addition, adipocytes release a wide array of signalling molecules, such as sphingolipids, as well as inflammatory and hormonal factors (adipokines) that are critical for interorgan crosstalk. The interactions of adipose tissue with the kidney - referred to as the adipo-renal axis - are important for normal kidney function as well as the response of the kidney to injury. Here, we discuss the mechanistic basis of this interorgan crosstalk, which clearly has great therapeutic potential given the increasing rates of chronic kidney disease secondary to obesity and type 2 diabetes mellitus.

Topics: Adipokines; Adiponectin; Adipose Tissue; AMP-Activated Protein Kinases; Angiotensin II; Angiotensinogen; Ceramidases; Diabetes Mellitus, Type 2; Humans; Inflammation; Kidney Diseases; Leptin; Macrophages; Obesity; Receptors, Adiponectin; Signal Transduction

Activation of the renin-angiotensin system has a pivotal role in the pathogenesis of diabetic complications. However, recent evidence suggests that it may also contribute to the development of diabetes itself. In the endocrine pancreas, all the components of an active renin-angiotensin system are present, which modulate a range of activities including local blood flow, hormone release and prostaglandin synthesis. In both types 1 and 2 diabetes, there is an up-regulation of its expression and activity in the endocrine pancreas. Whether these changes have a direct pathogenetic role or reflect a response to local stress or tissue injury remains to be established. Angiotensin-mediated increases in oxidative stress, inflammation and free fatty acids levels potentially contribute to beta-cell dysfunction in diabetes. In addition, activation of the renin-angiotensin system appears to potentiate the action of other pathogenic pathways including glucotoxicity, lipotoxicity and advanced glycation. In experimental models of type 2 diabetes, blockade of the renin-angiotensin system with angiotensin converting enzyme inhibitors or angiotensin receptor antagonists results in the improvement of islet structure and function. Moreover, the incidence of de novo diabetes appears to be significantly reduced by blockade of the renin-angiotensin system in clinical studies. At least two large controlled trials are currently underway to study the role of renin-angiotensin system in the development of diabetes. It is hoped that these studies will demonstrate the true potential of the blockade of the renin-angiotensin system for the prevention of diabetes.

Topics: Angiotensin I; Angiotensin II; Angiotensinogen; Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fibrosis; Humans; Hyperglycemia; Hypoglycemia; Islets of Langerhans; Pancreas; Peptidyl-Dipeptidase A; PPAR gamma; Receptors, Angiotensin; Renin; Renin-Angiotensin System

Genetic polymorphisms of factors regulating the function of endothelium and blood pressure are recently intensively studied also in type 2 diabetes because endothelial dysfunction and arterial hypertension are risk factors of atherosclerosis. The following review deals with relations of polymorphisms in the renin-angiotensin-aldosterone (RAAS) system, polymorphisms of NO-synthase (NOS) as well as the gene for atrial natriuretic peptide (hANP). So far most information was assembled on the influence of polymorphisms of RAAS genes, in particular the gene coding the angiotensin converting enzyme (ACE), on complications of type 2 diabetes. A relationship with the development of coronary disease was described in ACE genes, the receptor for angiotensin II--type 1 (AT1R), angiotensinogen and in several NOS polymorphisms. Also the relationship of polymorphisms of genes ACE, AT1R, NOS and hANP was described in relation to the development of hypertension which is an important risk factor for macrovascular and microvascular complications of diabetes. In some investigations the relationship of polymorphisms of ACE and AT1R genes and the development of diabetic nephropathy was described where a significant acceleration of the process of atherogenesis occurs. As type 2 diabetes mellitus and atherosclerosis are polygenically determinal diseases, it will be in particular necessary to investigate in future the concurrent influence of several gene polymorphisms and their interactions with the diabetic milieu intérieur on the development of macrovascular and microvascular complications of diabetes.

Topics: Angiotensinogen; Arteriosclerosis; Atrial Natriuretic Factor; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Humans; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors

According to the "thrifty-genotype" hypothesis proposed by Neel, diseases of civilization such as non-insulin-dependent diabetes mellitus and hypertension result from a discordance between certain features of our present-day environment and our genetic make-up which evolved to fit the life of Paleolithic humans. This concept implies that while "affected" individuals harbor the "original" ancestral version of the relevant genes, healthy or "unaffected" individuals have picked up recent mutations leading to a "loss of thriftiness" of these genes. Support for this concept now comes from recent studies of the angiotensinogen gene, where an ancestral variant of the gene (AGT 235T), also present in primates, has now been associated with hypertension whereas a neomorphic variant (AGT 235M) apparently reduces the risk of high blood pressure. The implications of these findings for our understanding and approach to the study of complex genetic diseases is discussed.

Topics: Angiotensinogen; Animals; Biological Evolution; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genetic Variation; Hominidae; Humans; Hypertension; Primates

In view of the known vasodilatory effects of glucagon-like peptide-1 and exenatide, we investigated the effects of exenatide on vasoactive factors. We analysed blood samples and mononuclear cells (MNCs) from a previous study, collected after a single dose and 12 weeks of exenatide or placebo treatment in a series of 24 patients with type 2 diabetes mellitus. After exenatide treatment, plasma concentrations of atrial natriuretic peptide, cyclic guanyl monophosphate (cGMP) and cyclic adenyl monophosphate increased significantly at 12 weeks. Plasma cGMP and adenylate cyclase expression in MNCs increased significantly after a single dose. Angiotensinogen concentration fell significantly 2 hours after a single dose and at 12 weeks, while renin and angiotensin II levels fell significantly only after a single dose and not after 12 weeks of treatment. Exenatide also suppressed the plasma concentration of transforming growth factor-β and the expression of P311 in MNCs at 12 weeks. Thus, exenatide induces an increase in a series of vasodilators, while suppressing the renin-angiotensin system. These changes may contribute to the overall vasodilatory effect of exenatide.

Topics: Adenylyl Cyclases; Angiotensinogen; Anti-Obesity Agents; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cyclic AMP; Cyclic GMP; Diabetes Mellitus, Type 2; Exenatide; Gene Expression Regulation; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Leukocytes, Mononuclear; Nerve Tissue Proteins; Obesity; Oncogene Proteins; Peptides; Renin-Angiotensin System; Reproducibility of Results; Single-Blind Method; Transforming Growth Factor beta; Venoms

Recently, it has been reported that urinary angiotensinogen levels is a specific index of the intrarenal renin-angiotensin-aldosterone system (RAAS) status and it is significantly correlated with urinary albumin:creatinine (Cr) ratio in hypertensive patients. The aim of the present study was to assess the effect of activation of the Vitamin D receptor with calcitriol on albuminuria and urinary angiotensinogen as a novel biomarker of the intra-renal RAAS status in patients with diabetic nephropathy (DN).. Ninety-eight patients with type 2 diabetes and albuminuria who were treated with RAAS inhibitors (angiotensin-converting enzyme inhibitor (ACE-i) or angiotensin receptor blocker (ARB)) have participated in this study. Patients were randomized to receive either placebo (n = 50) or 0.25 μg/day calcitriol (n = 48). We have examined urinary albumin:Cr ratio and urinary angiotensinogen:Cr ratio before and 24 weeks later after treatment in both group.. The mean urinary albumin:Cr ratio and urinary angiotensinogen:Cr ratio were significantly higher in patients with DN than in normal controls (p < 0.001). Urinary angiotensinogen:Cr ratio was significantly, positively correlated with urinary albumin:Cr ratio in both groups (in the placebo group; p = 0.01, r = 0.4236, in calcitriol group; p = 0.01, r = 0.4564).. These data indicated that administration of Vitamin D receptor activator in combination with RAAS inhibitors had an additional benefit in lowering albuminuria in patients with DN. More pronounced reduction of urinary albumin:Cr ratio that was positively correlated with angiotensinogen:Cr ratio in calcitriol group suggested that Vitamin D receptor activation might blunt albuminuria by reducing urinary angiotensinogen levels reflecting intra-renal RAAS status.

Topics: Albuminuria; Angiotensinogen; Calcitriol; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Male; Middle Aged; Receptors, Calcitriol; Renal Insufficiency, Chronic; Renin-Angiotensin System

In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity.. We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to <30 mg/g of albumin-to-creatinine ratio) or microalbuminuria (30 to <300 mg/g) to the DRI group or ARB group (any ARB) with a target blood pressure of <130/80 mmHg. The primary endpoint was a reduction in albuminuria.. Twelve patients dropped out during the observation period, and a total of 225 patients were analyzed. During the study period, the systolic and diastolic blood pressures were not different between the groups. The changes in the urinary albumin-to-creatinine ratio from baseline to the end of the treatment period in the DRI and ARB groups were similar (-5.5% and -6.7%, respectively). In contrast, a significant reduction in the urinary excretion of angiotensinogen was observed in the ARB group but not in the DRI group. In the subgroup analysis, a significant reduction in the albuminuria was observed in the ARB group but not in the DRI group among high-normal albuminuria patients.. DRI and ARB reduced albuminuria in hypertensive patients with type 2 diabetes. In addition, ARB, but not DRI, reduced albuminuria even in patients with normal albuminuria. DRI is not superior to ARB in the reduction of urinary excretion of albumin and angiotensinogen.

Topics: Albuminuria; Amides; Angiotensin Receptor Antagonists; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Prospective Studies; Renin; Renin-Angiotensin System; Treatment Outcome

Urinary levels of renin-angiotensin-aldosterone system (RAAS) components may reflect renal RAAS activity and/or the renal efficacy of RAAS inhibition. Our aim was to determine whether urinary angiotensinogen and renin are circulating RAAS-independent markers during RAAS blockade.. Urinary and plasma levels of angiotensinogen, renin, and albumin were measured in 22 patients with type 2 diabetes, hypertension, and albuminuria, during 2-month treatment periods with placebo, aliskiren, irbesartan, or their combination in random order in a crossover study.. Aliskiren and irbesartan both increased plasma renin 3-4-fold, and above 10-fold when combined. Irbesartan decreased plasma angiotensinogen by approximately 25%, and no changes in plasma angiotensinogen were observed during the combination. Urine contained aliskiren at micromolar levels, blocking urinary renin by above 90%. Both blockers reduced urinary angiotensinogen, significant for irbesartan only. Combination blockade reduced urinary angiotensinogen even further. Reductions in urinary angiotensinogen paralleled albuminuria changes, and the urine/plasma concentration ratio of angiotensinogen was identical to that of albumin under all conditions. In contrast, urinary renin did not follow albumin, and remained unaltered after all treatments. Yet, the urine/plasma concentration ratio of renin was more than 100-fold higher than that of angiotensinogen and albumin, and approximately 4-fold reduced by single RAAS blockade, and more than 10-fold by dual RAAS blockade.. Aliskiren filters into urine and influences urinary renin measurements. The urine/plasma renin ratio, but not urinary renin alone, may reflect the renal efficacy of RAAS blockade. Urinary angiotensinogen is a marker of filtration barrier damage rather than intrarenal RAAS activity.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Amides; Angiotensinogen; Angiotensins; Antihypertensive Agents; Biphenyl Compounds; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fumarates; Humans; Irbesartan; Male; Middle Aged; Renin; Renin-Angiotensin System; Tetrazoles

The effect of laughter therapy on the plasma levels of renin, angiotensinogen, and prorenin was investigated in patients with type 2 diabetes. In the diabetic patients, the mean plasma renin concentrations were 24.6+/-12.1 ng/ml/h in the first observation (at the beginning of laughter therapy), 8.2+/-3.4 ng/ml/h in the second observation (three months after the beginning of laughter therapy) and 7.7+/-1.7 ng/ml/h in the third observation (six months after the beginning of laughter therapy). The mean plasma angiotensinogen concentrations in the 1st, 2nd and 3rd observations were 0.19+/-0.08, 0.47+/-0.12, 0.42+/-0.14 microg/ml, respectively. The mean plasma prorenin concentrations in the 1st, 2nd and 3rd observations during the laughter therapy were 195.1+/-66.2, 193.4+/-88.2 and 170.7+/-52.5 pg/ml, respectively. Plasma renin concentrations were significantly decreased (p<0.05) by the therapy. Subnormal concentrations of plasma angiotensinogen were found in the 1st observation and increased significantly (p<0.05) to the normal range after the therapy. Plasma prorenin concentration only slightly changed during the laughter therapy. Other biochemical parameters remained unchanged during the laughter therapy. These results indicated that a long-term laughter therapy changed the plasma components of renin-angiotensin system in patients with diabetes. Thus, laughter therapy can be used as non-pharmacological treatment for the prevention of diabetic microvascular complications.

Topics: Angiotensinogen; Blood Chemical Analysis; Diabetes Mellitus, Type 2; Female; Humans; Laughter Therapy; Male; Middle Aged; Renin; Renin-Angiotensin System

We determined the relationship between the gene polymorphism of angiotensinogen (AGT), angiotensin-converting enzyme (ACE), or angiotensin II receptor (AT1R) and the progression of diabetic nephropathy in a multicenter trial of ethnically homogeneous Japanese patients with non-insulin-dependent diabetes (NIDDM). Gene polymorphism of ACE I/D, AGT M235T and AT1R A1166C was determined by polymerase chain reaction amplification using allele-specific primers. Japanese NIDDM patients (n = 1,152) were selected from several diabetic clinics. All patients were divided into three groups as follows: (1) group I (n = 407): normoalbuminuric patients; (2) group II (n = 327): microalbuminuric patients, and (3) group III (n = 418): overt albuminuric patients. Clinical factors for investigation in all patients were the date of birth, gender, levels of urinary albumin excretion, findings of the ocular fundus, duration of diabetes, hemoglobin A1c and blood pressure. It appears that genetic polymorphisms in the renin-angiotensin systems, i.e. ACE or AT1R, may affect the progression to renal failure of patients (especially females) with NIDDM.

Topics: Aged; Angiotensin II; Angiotensinogen; Diabetes Mellitus, Type 2; Disease Progression; DNA; Female; Genotype; Humans; Japan; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Receptors, Angiotensin

The main purpose of this randomized controlled study was to assess the effects of postmenopausal estrogen replacement therapy on blood pressure (BP) and plasma renin substrate (PRS) in non insulin-dependent diabetic patients (DNID). We randomized 32 postmenopausal DNID (mean age: 55.3 +/- 4.2 years) into two groups: 16 women were untreated, and 16 received percutaneous estradiol (E2) 17 beta and natural progesterone for 6 months. Systolic (SBP) and diastolic (DBP) blood pressure were monitored by an automatic device at inclusion and on the 1st, 3rd and 6th months of therapy. Treatment efficacy was proven by significant E2 plasma increase to 92.2 +/- 13.4 pg/ml in the treated group, which is a sufficient level for preventing postmenopausal osteoporosis. No significant inter or or intra-individual variation in SBP or DBP was observed in either group. The same stability was noted for plasma renin substrate. No significant difference was noted between the two groups in terms of body weight, fructosamine and glycosylated hemoglobin A1c after 1, 3 and 6 months. There was also no change in plasma levels of total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and apolipoproteins A1 and B. All the patients who received replacement therapy wished to continue treatment. We conclude that the association of percutaneous E2 17 beta and natural progesterone had no deleterious effects, in diabetic patients, on BP, carbohydrate and lipoprotein metabolism. Thus this postmenopausal replacement therapy appears preferable in this vascular high risk population, particularly since estrogens via the parenteral route may have an antiatherogenic effect by direct action on the vessel walls.

Topics: Administration, Cutaneous; Administration, Oral; Angiotensinogen; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Estradiol; Female; Humans; Lipoproteins; Menopause; Middle Aged; Progesterone

Diabetic nephropathy is one of the major complications of Type 2 diabetes mellitus. In this study, we aimed to investigate the effects of angiotensinogen M235T/T174M and angiotensin type 1 receptor A1166C gene polymorphisms on the development of diabetic nephropathy in patients with type 2 diabetes mellitus.. This study included 100 type‑2 diabetes mellitus patients with diabetic nephropathy patients (patient group) and 99 type‑2 diabetes mellitus patients without diabetic nephropathy (control group). Polymerase chain reaction and restriction fragment length polymorphism methods were used to identify polymorphisms in the angiotensinogen M235T/T174M and angiotensin type 1 receptor A1166C genes.. There was no significant difference in genotype frequencies of M235T gene polymorphism between patient and control groups (χ2 = 4.01, df = 2, p = 0.13). There was no significant difference in genotype frequencies of T174M gene polymorphism between patient and control groups (X2 = 0.36, df = 2, p = 0.83). There was no significant difference in genotype frequencies of A1166C gene polymorphism between patient and control groups (χ2 = 0.51, df = 2, p = 0.77).. The results showed no significant difference in angiotensinogen M235T/T174M and angiotensin type 1 receptor A1166C gene polymorphisms between the patient and control groups. Future studies are needed to validate the results of this study and to explore underlying mechanisms (Tab. 3, Fig. 3, Ref. 35). Text in PDF www.elis.sk Keywords: type 2 diabetes mellitus, diabetic nephropathy, angiotensinogen gene polymorphism, angiotensin type 1 receptor, gene polymorphism.

Topics: Angiotensinogen; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Genotype; Humans; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1

Hypertension (HTN) is a multifactorial chronic disease that poses a significant global health burden and is associated with increased mortality rates. It often coexists with other conditions, such as cardiovascular, liver, and renal diseases, and has a strong association with diabetes mellitus. Insulin resistance and endothelial dysfunction commonly occur in individuals with both HTN and type 2 diabetes mellitus (T2DM). Genetic factors, along with environmental and pathological factors, play a role in the development of HTN. Recent studies have revealed the influence of single nucleotide polymorphisms (SNPs) in various genes on HTN. In this study, we aimed to investigate the genetic polymorphism of angiotensinogen (AGT) T174M (rs4762) and its association with HTN in diabetic patients.. A total of 300 participants were enrolled in this study and divided into three groups: control, hypertensive, and hypertensive diabetic. Blood samples were collected, and predetermined biochemical parameters were assessed. Genotyping of the AGT T174M (rs4762) gene was conducted using Tetra ARMS PCR with specific primers.. The study findings revealed a significant association between AGT T174M (rs4762) genotype and HTN in diabetic patients within the Pakistani population. The C/T genotype of AGT T174M (rs4762) was found to be significant in both the hypertensive and hypertensive diabetic participants compared to the control group. This genotype was identified as a risk factor for developing HTN in both the hypertensive and hypertensive diabetic participants.. This study demonstrates a significant association between AGT T174M (rs4762) genetic polymorphism and HTN in diabetic patients. The C/T genotype of AGT T174M (rs4762) may serve as a potential marker for identifying individuals at risk of developing HTN, specifically in the hypertensive and hypertensive diabetic populations. Further research is warranted to elucidate the underlying mechanisms and validate these findings in larger cohorts.

Topics: Angiotensinogen; Diabetes Mellitus, Type 2; Humans; Hypertension; Insulin Resistance; Polymorphism, Single Nucleotide

The study aim was to analyse the frequency of polymorphic variants of angiotensinogen gene polymorphism (AGT 704T>C, rs699) in essential arterial hypertension (EAH) patients.. Seventy-two individuals with EAH and hypertension‑mediated organ damage (stage 2), moderate, high or very high cardiovascular risks were involved in the case-control study. Among them, 70.84 % (51) were females and 29.16 % (21) were males; mean age was 59.87±7.98 y. The control group consisted of fifty practically healthy individuals at relevant age (49.13±6.28 y) and with relevant sex distribution (62 % were females, 38 % were males). AGT (704T>C) gene polymorphism was examined by RT-PCR.. The distribution of genotypes in the study group was as follows: TT - 14 %, TC - 60 %, CC - 26 %, which corresponded to the distribution in the control group - 16 %, 54 % and 30 %, respectively, and did not deviate from the Hardy-Weinberg equilibrium. Smoking, type 2 diabetes mellitus (DM2) and obesity increased the relative risk of EAH in the examined population 2.5 times [OR=2.81; p=0.049], 3.75 times [OR=4.68; p=0.005] and almost twofold [OR=2.90; p=0.004], respectively. The probability of EAH increases fourfold with the angiotensin II elevation in the serum. Genotypes and alleles of the AGT (704T>C) gene were not significant risk factors for EAH and DM2 in the studied population. However, the TC-genotype (lesser T-allele) increases the risk of obesity in EAH patients more than 1.5 times [OR=2.93; p=0.03]. In addition, the T-allele increases the risk for blood pressure (BP) to elevate up to grade 2-3 [OR=3.64; p < 0.001].. One-way ANOVA analysis confirmed the AGT (704T>C) gene polymorphism to be associated with systolic and diastolic BP elevation (F=7.80; p < 0.001 and F=4.90; p=0.01, respectively), especially in TT-genotype carriers (p < 0.05), and with body mass index increase, albeit only in women (F=13.94; p < 0.001) (Tab. 4, Fig. 3, Ref. 26). Text in PDF www.elis.sk Keywords: angiotensinogen gene (AGT 704T>C), diabetes mellitus type 2, arterial hypertension, obesity, risk.

Topics: Aged; Angiotensinogen; Blood Pressure; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genotype; Humans; Hypertension; Male; Middle Aged; Obesity; Polymorphism, Genetic

Since angiotensinogen has a pivotal role in the renin-angiotensin-aldosterone system, the analysis of polymorphisms of the angiotensinogen (AGT) gene could help explain its potential involvement in hypertension and diabetic nephropathy (DN) pathogenesis. For that reason, we investigated 1) the association of AGT rs4762 with blood pressure (BP) and kidney function-related traits and 2) the interaction effect of AGT rs4762 with DN on BP and kidney function-related traits in 546 Mexican adults with type 2 diabetes (T2D).. We enrolled 546 unrelated Mexican patients with T2D (350 cases with DN and 196 controls without DN). AGT rs4762 was genotyped in all participants using TaqMan technology (effect allele: A). BP and kidney function-related traits, including serum urea and creatinine, urinary albumin, urine albumin to urine creatinine ratio (ACR), and glomerular filtration rate, were studied. DN was defined as having a previous diagnosis of T2D and an ACR ≥ 30 mg/g. The association between these parameters was investigated using logistic regression with adjustment for covariates.. AGT rs4762 A allele was significantly associated with diastolic blood pressure (N = 546, β = 1.243 ± 0.918, p = 0.029). A significant interaction between DN and AGT rs4762 was also observed in relation to diastolic blood pressure (DBP) (N = 546, β = 0.930 ± 0.433, p=0.032). A follow-up analysis of simple effects particularly revealed a positive association between AGT rs4762 A allele and DBP only in patients with diabetic nephropathy (N = 350, β = 2.837 ± 1.267, p = 0.026).. Our results evidence that, although AGT rs4762 is not associated with DN, the AGT rs4762 A allele is positively associated with DBP in the Mexican population with DN.

Topics: Adult; Albumins; Angiotensinogen; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Mexico; Renin-Angiotensin System

Objective The intrarenal renin-angiotensin system (RAS) is activated in patients with chronic kidney disease (CKD), and urinary angiotensinogen (AGT) levels, a surrogate marker of the intrarenal RAS activation, are associated with blood pressure (BP) and urinary albumin excretion. In addition, it has been shown that changes in urinary AGT levels correlate with annual changes in the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes and that elevated levels of urinary AGT in type 2 diabetic patients with albuminuria are a high-risk factor for worsening renal and cardiovascular complications. However, whether or not baseline urinary AGT levels predict deterioration of the kidney function in all patients with CKD is unclear. Methods We recruited 62 patients with CKD whose eGFR was >15 mL/min/1.73 m

Topics: Angiotensinogen; Diabetes Mellitus, Type 2; Humans; Kidney; Renal Insufficiency, Chronic; Renin-Angiotensin System

Type 2 diabetes mellitus (T2DM) and hypertension are common chronic diseases mainly associated with the development and progression of end-stage renal disease (ESRD) leading to morbidity and mortality. Gene polymorphisms linked to the renin-angiotensin (

Topics: Aged; Angiotensinogen; Diabetes Mellitus, Type 2; Egypt; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Mutation, Missense; Polymorphism, Single Nucleotide

During type 2 diabetes (T2D) and hypertension there is stimulation of renal proximal tubule angiotensinogen (AGT), but whether urinary excretion of AGT (uAGT) is an indicator of glomerular damage or intrarenal RAS activation is unclear. We tested the hypothesis that elevations in uAGT can be detected in the absence of albuminuria in a mouse model of T2D.. Male C57BL/6 mice (N = 10) were fed a high fat (HFD; 45% Kcal from fat) for 28 weeks, and the metabolic phenotype including body weight, blood pressures, glucose, insulin, ippGTT, HOMA-IR, and cholesterol was examined. In addition, kidney Ang II content and reactive oxygen species (ROS) was measured along with urinary albumin, creatinine, Ang II, and AGT.. All parameters consistent with T2D were present in mice after 12-14 weeks on the HFD. Systolic BP increased after 18 weeks in HFD but not NFD mice. Intrarenal ROS and Ang II concentrations were also increased in HFD mice. Remarkably, these changes paralleled the augmentation uAGT excretion (3.66 ± 0.50 vs. 0.92 ± 0.13 ng/mg by week 29; P < 0.01), which occurred in the absence of overt albuminuria.. In HFD-induced T2D mice, increases in uAGT occur in the absence of overt renal injury, indicating that this biomarker accurately detects early intrarenal RAS activation.

Topics: Albuminuria; Angiotensinogen; Animals; Biomarkers; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Hypertension; Male; Mice; Mice, Inbred C57BL; Obesity; Renin-Angiotensin System

Youth with type 2 diabetes (T2D) have high rates of obesity, hypertension and suboptimal glycemic control. We hypothesized that renin-angiotensin system (RAS) activation is present in youth with T2D and associated with poor glycemic control and renal outcomes.. Cross-sectional analysis of 183 youth with T2D and 100 controls from the Improving renal Complications in Adolescents with T2D through REsearch cohort. Diabetes youth stratified by urine albumin:creatinine ratio (ACR) < or ≥2 mg/mmol. RAS levels measured with enzyme-linked immunosorbent assay (ELISA) and enzyme activities by synthetic substrates. In T2D, levels log transformed and Tobit linear regressions evaluated for associations with hemoglobin A1c (HbA1c), mean arterial pressure (MAP), estimated glomerular filtration rate (eGFR), ACR.. Youth were 14 to 15 years, with diabetes duration 1.7 to 1.8 years; 21.3% albuminuria. Serum: differences in plasma renin activity (<0.0001), and angiotensin converting enzyme (ACE) activity (P = .003) in T2D vs controls. Urine: higher ACE activity and ACE2 protein/activity (all P < .0001) in T2D, higher levels in T2D with albuminuria. Multivariable regressions: higher serum ACE activity (ß = 0.03, SE 0.01;P < .01), urine ACE activity (ß = 0.44, SE 0.18;P < .01), ACE2 (ß = 0.51, SE 0.19;P < .01) positively associated with HbA1c; urine angiotensinogen (AGT) negatively associated (ß = -0.28 [SE 0.06;P < .01]). Higher serum aldosterone (ß = 0.11 [SE 0.04;P < .01]) and urine AGT (ß = 0.32 [SE 0.07;P < .01]) significantly associated with ACR and urine ACE2 (ß = 0.21 [SE 0.13;P < .03]). No associations between RAS markers and eGFR/MAP.. RAS activation present in youth with T2D and associated with higher HbA1c. Higher serum aldosterone and urine AGT associated with albuminuria. The prognostic significance of the combined effect of glycemia and RAS activation on renal outcomes requires additional investigation.

Topics: Adolescent; Albuminuria; Aldosterone; Angiotensin-Converting Enzyme 2; Angiotensinogen; Biomarkers; Blood Glucose; Blood Pressure; Canada; Case-Control Studies; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Glycemic Control; Humans; Male; Peptidyl-Dipeptidase A; Renin; Renin-Angiotensin System

The renin-angiotensin system (RAS) is important in the onset and course of cardiovascular, kidney, and metabolic disorders. Previous reports showed that the RAS blockade protects organs and suppress the development of type 2 diabetes mellitus. A novel component of the RAS, namely, chromosome 9 open reading frame 3 (C9orf3), was recently identified, however, its effects are unclear. We evaluated whether the genetic variant of C9orf3 is associated with morbidity of hypertension among subjects with type 2 diabetes. We enrolled 382 subjects with type 2 diabetes, 222 of whom were diagnosed with hypertension. Human leukocyte genomic DNA was isolated and a genetic variant was analyzed for a C/T variant of C9orf3 (rs4385527) via PCR analysis. The relationship between the genotype and hypertension morbidity among subjects with diabetes was examined. The proportion of the respective C9orf3 genetic variants were as follows 247 CC, 119 CT, and 16 TT. The risk of hypertension was determined to be 1.58, with a 95% confidence interval of 1.11-2.27. Moreover, the p value was 0.012 for allelic comparison and for Armitage's trend test, with the C allele identified as the risk factor. Consequently, hypertension was markedly associated with type 2 diabetes in subjects with the C9orf3 variant, exhibiting a nearly 1.6-fold increased risk. The C variant of a new component of the RAS, C9orf3 (rs4385527) might have a considerable impact on the pathogenesis of hypertension in diabetes.

Topics: Alleles; Aminopeptidases; Angiotensinogen; Blood Pressure; Cohort Studies; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

(1) Aims: Diabesity, defined as diabetes occurring in the context of obesity, is a serious health problem that is associated with an increased risk of premature heart attack, stroke, and death. To date, a key challenge has been to understand the molecular pathways that play significant roles in diabesity. In this study, we aimed to investigate the genetic links between diabetes and obesity in diabetic individuals and highlight the role(s) of shared genes in individuals with diabesity. (2) Methods: The interactions between the genes were analyzed using the Search Tool for the Retrieval of Interacting Genes (STRING) tool after the compilation of obesity genes associated with type 1 diabetes (T1D), type 2 diabetes (T2D), and maturity-onset diabetes of the young (MODY). Cytoscape plugins were utilized for enrichment analysis. (3) Results: We identified 546 obesity genes that are associated with T1D, T2D, and MODY. The network backbone of the identified genes comprised 514 nodes and 4126 edges with an estimated clustering coefficient of 0.242. The Molecular Complex Detection (MCODE) generated three clusters with a score of 33.61, 16.788, and 6.783, each. The highest-scoring nodes of the clusters were

Topics: Adipocytes; Angiotensinogen; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fibrinogen; Gene Regulatory Networks; Lipolysis; Obesity; Oxidative Stress; Receptor, IGF Type 1; Receptors, LDL; Renin; Shc Signaling Adaptor Proteins

Topics: Angiotensinogen; Animals; Canagliflozin; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glucose; Hypertension; Kidney; Mice; Sodium

Hypertension and renal injury are common complications of type 2 diabetes mellitus (T2DM). Hyperglycemia stimulates renal proximal tubular angiotensinogen (AGT) expression via elevated oxidative stress contributing to the development of high blood pressure and diabetic nephropathy. The sodium glucose cotransporter 2 (SGLT2) in proximal tubules is responsible for the majority of glucose reabsorption by renal tubules. We tested the hypothesis that SGLT2 inhibition with canagliflozin (CANA) prevents intrarenal AGT augmentation and ameliorates kidney injury and hypertension in T2DM.. We induced T2DM in New Zealand obese mice with a high fat diet (DM, 30% fat) with control mice receiving regular fat diet (ND, 4% fat). When DM mice exhibited > 350 mg/dL blood glucose levels, both DM- and ND-fed mice were treated with 10 mg/kg/day CANA or vehicle by oral gavage for 6 weeks. We evaluated intrarenal AGT, blood pressure, and the development of kidney injury.. Systolic blood pressure in DM mice (133.9 ± 2.0 mm Hg) was normalized by CANA (113.9 ± 4.0 mm Hg). CANA treatment ameliorated hyperglycemia-associated augmentation of renal AGT mRNA (148 ± 21 copies/ng RNA in DM, and 90 ± 16 copies/ng RNA in DM + CANA) and protein levels as well as elevation of urinary 8-isoprostane levels. Tubular fibrosis in DM mice (3.4 ± 0.9-fold, fibrotic score, ratio to ND) was suppressed by CANA (0.9 ± 0.3-fold). Furthermore, CANA attenuated DM associated increased macrophage infiltration and cell proliferation in kidneys of DM mice.. CANA prevents intrarenal AGT upregulation and oxidative stress and which may mitigate high blood pressure, renal tubular fibrosis, and renal inflammation in T2DM.

Topics: Angiotensinogen; Animals; Blood Glucose; Blood Pressure; Canagliflozin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diet, High-Fat; Fibrosis; Humans; Hypertension; Kidney Tubules, Proximal; Mice; Oxidative Stress; Sodium-Glucose Transporter 2 Inhibitors; Up-Regulation

Novel potential tubular biomarkers in diabetic nephropathy could improve risk stratification and prediction. The study aimed to evaluate the association of tubular damage markers with rapid renal progression and incidence of end stage renal disease (ESRD) in type 2 diabetes (T2DM).. A prospective cohort study, involving a total of 257 patients with T2DM, was included. The baseline values of urine albumin, cystatin-C, angiotensinogen, kidney injury molecule-1 (KIM-1) and neutrophil-gelatinase associated lipocalin (NGAL) were measured. The composite outcomes included a rapid glomerular filtration rate (GFR) decline or incident of ESRD at 3-year follow-up.. The composite outcomes were noted in 26.1%. Using univariate followed by multivariate COX proportional hazard regression analysis, the patients with highest quartiles of urine cystatin-C (HR 2.96, 95% CI, 1.38-6.35), urine angiotensinogen (HR 2.93, 95% CI, 1.40- 6.13) urine KIM-1 (HR 2.77, 95% CI, 1.27-6.05) and urine NGAL (HR 2.53, 95% CI, 1.11-5.76) were significantly associated with rapid renal progression when compared with the patients with the lowest quartiles of all tubular biomarkers.. Patients with T2DM with high levels of baseline urine tubular biomarkers (cystatin-C, angiotensinogen, KIM-1 and NGAL) had a greater incidence of ESRD and rapid GFR decline.

Topics: Aged; Albuminuria; Angiotensinogen; Biomarkers; Cohort Studies; Cystatin C; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Female; Glomerular Filtration Rate; Hepatitis A Virus Cellular Receptor 1; Humans; Kidney Failure, Chronic; Kidney Tubules; Lipocalin-2; Male; Middle Aged; Prospective Studies; Sensitivity and Specificity

Topics: Albuminuria; Angiotensinogen; Diabetes Mellitus, Type 2; Glucose; Humans; Hypoglycemic Agents; Sodium

Despite the progress in the treatment of HF, its prognosis remains disappointing primarily due to the fact that important subgroups of patients with HF are not sufficiently investigated. This also applies to patients with HF and background metabolic disorders, in particular, type 2 diabetes. It is known that the polymorphism of the rs699 marker of the M235T ATG gene is associated with a tendency to arterial hypertension, coronary heart disease and atrial fibrillation. A relationship was found between the polymorphism of M235T and the risk of HF development. One of the promising new biomarkers is the fibrosis marker ST2. The purpose of our study was to evaluate the role of the biomarker ST2 and the genetic polymorphism of the AT2 gene M235T in the progression of CHF and the development of adverse events in patients with concomitant type 2 diabetes. We found that patients with HFpEF and T2DM with ATG TT + MT genotype have a higher level of ST2 and a higher probability of unfavorable cardiovascular events during 24 months of observation compared with MM genotype carriers.

Topics: Aged; Angiotensinogen; Biomarkers; Blood Glucose; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Disease Progression; Female; Fibrosis; Follow-Up Studies; Gene Expression; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Male; Middle Aged; Polymorphism, Genetic; Prognosis; Survival Analysis; Triglycerides; Walk Test

Urinary angiotensinogen (AGT) is potentially a specific biomarker for the status of the intrarenal renin-angiotensin system (RAS) in patients with diabetes mellitus. We explored whether changes in urinary AGT excretion levels were associated with the deterioration of kidney function in type 2 diabetes patients with preserved kidney function. Urinary baseline AGT levels were measured in 118 type 2 diabetic patients who were not taking RAS blockers and who had estimated glomerular filtration rates (eGFRs) ≥ 60 mL/min/1.73 m². A total of 91 patients were followed-up for 52 months. Changes in urinary levels of AGT (ΔAGT) were calculated by subtracting urinary AGT/creatinine (Cr) at baseline from urinary AGT/Cr after 1 year. ΔAGT was significantly inversely correlated with annual eGFR change (β = -0.29, P = 0.006; β = -0.37, P = 0.001 after adjusting for clinical factors). RAS blockers were prescribed in 36.3% of patients (n = 33) during follow-up. The ΔAGT values were lower in the RAS blockers users than in the non-RAS blockers users, but the differences were not statistically significant (7.37 ± 75.88 vs. 22.55 ± 57.45 μg/g Cr, P = 0.081). The ΔAGT values remained significantly correlated with the annual rate of eGFR change (β = -0.41, P = 0.001) in the patients who did not use RAS blockers, but no such correlation was evident in the patients who did. ΔAGT is inversely correlated with annual changes in eGFR in type 2 diabetes patients with preserved kidney function, particularly in RAS blocker-naïve patients.

Topics: Adult; Albuminuria; Angiotensin Receptor Antagonists; Angiotensinogen; Creatinine; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Renin-Angiotensin System

Gene polymorphisms associated with the renin-angiotensin-aldosterone system (RAAS) have been extensively studied in diabetic nephropathy (DN) patients, due to therapeutic potential of targeting the RAAS and slowing down the disease progression. The aim of our study was to examine the association between angiotensinogen (AGT) gene polymorphisms (rs699 and rs4762) and DN in Caucasians with type 2 diabetes mellitus (T2DM). A total of 651 unrelated Slovenian (Caucasian) T2DM patients were tested for AGT rs699 and rs4762 polymorphisms using a novel fluorescence-based kompetitive allele-specific polymerase chain reaction (KASPar) assay. A study group consisted of 276 T2DM patients with DN, while control group included 375 patients without DN but who have had T2DM for >10 years. For rs699 polymorphism, the frequencies of GG, GA and AA genotypes were 20.6%, 52.2% and 27.2%, respectively in T2DM patients and 23.4%, 48.1% and 28.5%, respectively in controls. The distributions of GG, GA and AA genotypes for rs4762 polymorphism were 73.9%, 23.2% and 2.9%, respectively in T2DM patients and 70.4%, 27.5% and 2.1%, respectively in controls. No significant differences in the allele frequencies were found between T2DM patients and controls for both polymorphisms. AGT rs699 and rs4762 missense polymorphisms are not associated with DN in our subset of Slovenian T2DM patients.

Topics: Aged; Angiotensinogen; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Male; Middle Aged; Mutation, Missense; Polymorphism, Genetic; Renin-Angiotensin System; Slovenia; White People

We conducted a descriptive case study to examine the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on urinary angiotensinogen excretion, which represents the function of the intrarenal renin-angiotensin system, in patients with type 2 diabetes. An SGLT2 inhibitor (canagliflozin 100 mg/day, ipragliflozin 25 mg/day, dapagliflozin 5 mg/day, luseogliflozin 2.5 mg/day or tofogliflozin 20 mg/day) was administered for 1 month (n=9). ELISA kits were used to measure both urinary intact and total angiotensinogen levels. Treatment with SGLT2 inhibitors significantly decreased hemoglobin A1c, body weight, systolic blood pressure and diastolic blood pressure (8.5±1.3 to 7.5%±1.0%, 82.5±20.2 to 80.6±20.9 kg, 143±8 to 128±14 mm Hg, 78±10 to 67±9 mm Hg, p<0.05, respectively), while urinary albumin/creatinine ratio was not significantly changed (58.6±58.9 to 29.2±60.7 mg/g, p=0.16). Both total urinary angiotensinogen/creatinine ratio and intact urinary angiotensinogen/creatinine ratio tended to decrease after administration of SGLT2 inhibitors. However, these changes were not significant (p=0.19 and p=0.08, respectively). These data suggest that treatment with SGLT2 inhibitors does not activate the intrarenal renin-angiotensin system in patients with type 2 diabetes.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensinogen; Blood Glucose; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diastole; Female; Humans; Male; Middle Aged; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Systole

A positive family history is recognized as an important risk factor for type 2 diabetes mellitus (T2DM), but the association of family history with rennin-angiotensin system (RAS) gene polymorphisms has not been reported yet, thus we aim to investigate it.Family history records, clinical and biochemical data were obtained from 1239 T2DM patients. Polymerase chain reaction (PCR) was performed for angiotensin-converting enzyme (ACE) genotyping and PCR-restricted fragment length polymorphism was used for angiotensinogen (AGT) genotyping.Patients with a negative family history had higher level of triglyceride and blood pressure, whereas those with a positive family history showed younger onset age and lower body mass index value (All P < .05), these findings were age-dependent. The percentage of hypertension was lower with a higher percentage of overweight among the patients with a positive family history (All P < .05). Patients with a positive family history and those with a negative family history had comparable genotype and allele distribution of ACE gene insertion/deletion polymorphisms and AGT gene M/T polymorphisms.A positive family history of diabetes was not associated with the RAS gene polymorphisms.

Topics: Adult; Age Factors; Angiotensinogen; Asian People; Blood Pressure; Body Mass Index; China; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genotype; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Restriction Fragment Length; Triglycerides

Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls for AGT variants (P = 0.05) but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15-3.20, permuted P = 0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk.

Topics: Alleles; Angiotensinogen; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

The aims of this study were (1) to examine the renoprotective effects of alogliptin and (2) to establish urinary angiotensinogen (AGT) as a prognostic marker of renoprotective effects of alogliptin in patients with type 2 diabetes (T2D).. In 43 patients with T2D (18 women, 66.1 ± 1.71 years), 25 mg/day of alogliptin was added to the traditional hypoglycemic agents and/or nondrug treatments. Urinary concentrations of albumin (Alb) and AGT, normalized by urinary concentrations of creatinine (Cr) (UAlbCR and UAGTCR, respectively), were measured before and after the 12-week alogliptin treatment.. Alogliptin treatment tended to decrease UAlbCR (99.6 ± 26.8 versus 114.6 ± 36.0 mg/g Cr, P = 0.198). Based on % change in UAlbCR, patients were divided into two groups, responders (< -25%) and nonresponders (≥ -25%), and a logistic analysis of UAGTCR before treatment showed cutoff value of 20.8 µg/g Cr. When all patients were redivided into two groups, those with higher values of UAGTCR before the treatment (Group H, n = 20) and those with lower values (Group L), Group H showed significantly decreased UAlbCR in response to alogliptin (-14.6 ± 8.6 versus +22.8 ± 16.8%, P = 0.033).. Urinary AGT could be a prognostic marker of renoprotective effects of alogliptin in patients with T2D.

Topics: Aged; Albumins; Angiotensinogen; Biomarkers; Creatinine; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Japan; Kidney; Kidney Diseases; Logistic Models; Male; Middle Aged; Piperidines; Prognosis; Treatment Outcome; Uracil

It was previously reported that intrarenal renin angiotensin system (RAS) plays a pivotal role in the onset and progression of diabetic nephropathy (DN). Urinary angiotensinogen (UAGT) was employed as a special index of the intrarenal RAS status and enhanced significantly at a very early stage of chronic kidney disease and type 1 diabetes. On the basis of these findings, the present study was performed to test the hypothesis that UAGT levels are increase even before the development of DN in type 2 diabetic patients without hypertension. 102 patients with type 2 diabetes mellitus (T2DM) and 18 healthy volunteers were studied cross-sectionally. Clinical data were collected and morning spot urine samples were obtained from all participants. UAGT levels were detected by an enzyme-linked immunosorbent assay (ELISA). As a result, UAGT to creatinine ratio (UAGT/Cr) was significantly enhanced in T2DM patients before the appearance of urinary albumin (UALB) and further increased to a greater degree in albuminuric patients. UAGT/Cr levels were positively correlated with Log (UALB to creatinine ratio) and diastolic blood pressure, but negatively correlated with estimated glomerular filtration rate. These data indicate that elevated UAGT levels precede the onset of albuminuria in normotensive T2DM patients. UAGT might potentially serve as an early marker to determine intrarenal RAS activity and predict progressive kidney disease in T2DM patients without hypertension.

Topics: Adult; Aged; Albuminuria; Angiotensinogen; Biomarkers; Blood Pressure; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged

The aim of the current study was to investigate the association between the InDel polymorphism in the angiotensin I-converting enzyme gene (ACE) and the rs699 polymorphism in the angiotensinogen gene (AGT) and diabetes mellitus type 2 (DM2) in a sample population from Southern Brazil. A case-control study was conducted with 228 patients with DM2 and 183 controls without DM2. The ACE InDel polymorphism was genotyped by polymerase chain reaction (PCR) with specific primers, followed by electrophoresis on 1.5% agarose gel. The AGT rs699 polymorphism was genotyped using a real-time PCR assay. No significant association between the ACE InDel polymorphism and DM2 was detected (P = 0.97). However, regarding the AGT rs699 polymorphism, DM2 patients had a significantly higher frequency of the AG genotype and lower frequency of the GG genotype when compared to the controls (P = 0.03). Our results suggest that there is an association between the AGT rs699 polymorphism and DM2 in a Brazilian sample.

Topics: Aged; Alleles; Angiotensinogen; Brazil; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gene Expression; Gene Frequency; Genetic Predisposition to Disease; Humans; INDEL Mutation; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System; Risk Factors

Recent genome-wide association studies have identified multiple variants that confer risk of type 2 diabetes mellitus (DM). However, established associations explain only a part of the heritability. Thus, even at the genome-wide association studies era, candidate gene approach should be still useful. Recent interventional studies against the renin-angiotensin system (RAS) showed reduction in new onset of DM, implying the system is involved in the onset. We substantiated the hypothesis that genetic variants of RAS have significant association with prevalence of DM. We enrolled to the study consecutive 782 subjects who had consulted our hospitals for mainly lifestyle related diseases. They consisted of 282 (36.1 %) diabetes cases. Genotypes were assayed with genomic DNA for conventional four genes of the RAS, i.e., angiotensin converting enzyme (ACE) insertion/deletion variant, angiotensinogen (AGT) M235T variant, angiotensin II type I receptor (AT1) A1166C variant, and aldosterone synthase (CYP11B2) C-344T variant. Association between the genetic variants of the RAS and prevalence of type 2 DM was tested. A significant association of DM and CYP11B2 genotype was obtained. There was no significant association between DM and ACE, AGT and AT1 variants. A multivariate logistic regression showed that age, gender, and CYP11B2 genotype were independent factors for association to diabetes, the DM risk of CC/CT to TT being 1.40 (95 % CI 1.04-1.90, p = 0.029). Thus, it is concluded that a genetic variant of the RAS should have a modest but significant impact on the onset of type 2 diabetes mellitus.

Topics: Aged; Aged, 80 and over; Angiotensinogen; Cytochrome P-450 CYP11B2; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System

The renin-angiotensin system (RAS) plays an important role in the pathogenesis of diabetic nephropathy. The aim of the present study was to investigate intrarenal RAS activity in patients with type 2 diabetes (T2DM).. We measured urinary angiotensinogen, a reliable biomarker of intrarenal RAS activity, in 14 controls without T2DM, 25 T2DM patients without nephropathy, 11 chronic kidney disease (CKD) patients without T2DM and 46 CKD patients with T2DM. Associations between urinary angiotensinogen and clinical parameters were examined.. Compared with the controls, urinary [angiotensinogen:creatinine] were significantly higher in T2DM patients without nephropathy (4.70 ± 2.22 vs. 8.31 ± 5.27 μg/g, p=0.037). Age, hemoglobin A1c (HbA1c) and fasting plasma glucose correlated significantly and positively with the log{urinary [angiotensinogen:creatinine]} (r=0.632, p=0.007; r=0.405, p=0.027; r=0.583, p=0.003, respectively) in T2DM patients without nephropathy. In contrast, the urinary [angiotensinogen:creatinine] were not significantly different between CKD patients with and without T2DM (22.7 ± 27.8 vs. 33.5 ± 40.8 μg/g, p=0.740); although they were significantly higher when compared with non-CKD patients. In the CKD patients with T2DM systolic blood pressure, serum creatinine, estimated glomerular filtration rate and urinary [albumin:creatinine] correlated significantly with the log{urinary [angiotensinogen:creatinine]} (r=0.412, p=0.004; r=0.308, p=0.037; r=-0.382, p=0.001; r=0.648, p<0.001, p<0.001, respectively).. Our findings indicate that poor glycemic control is significantly associated with intrarenal RAS activity in T2DM patients without nephropathy, and that decreased renal function is significantly associated with intrarenal RAS activity in CKD patients with T2DM.

Topics: Aged; Angiotensinogen; Biomarkers; Blood Glucose; Case-Control Studies; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Follow-Up Studies; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Kidney Function Tests; Male; Middle Aged; Renal Insufficiency, Chronic; Renin-Angiotensin System

Familial clustering and presumed genetic risk for type 2 diabetic (T2D) and non-diabetic end-stage kidney disease (ESKD) appear strong in African Americans. Examination of exome sequencing data in African American T2D-ESKD cases and non-diabetic non-nephropathy controls identified two low-frequency variants in the RREB1 gene, a repressor of the angiotensinogen (AGT) gene previously associated with kidney function, as being associated with T2D-ESKD: rs9379084 (P = 0.00087, OR = 0.26; D1171N) and rs41302867 (P = 0.00078, OR = 0.21; splice site variant). Rs41302867 replicated association in an independent sample of African Americans with T2D-ESKD [rs41302867 P = 0.033 (OR = 0.50)], and a trend towards rs9379084 association was observed (P = 0.070). In European Americans with T2D-ESKD compared with European American population based controls, both RREB1 variants replicated association [rs9379084 P = 1.67 × 10(-4) (OR = 0.54) and rs41302867 P = 0.013 (OR = 0.69)]. Rs9379084 was not associated with non-T2D-ESKD or T2D in African Americans (P = 0.55 and P = 0.37, respectively), but was associated with T2D in European Americans (P = 0.014, OR = 0.65). In African Americans, rs41302867 was associated with non-T2D-ESKD [P = 0.036 (OR = 0.54)] and hypertension attributed ESKD [H-ESKD, P = 0.029 (OR = 0.50)]. A meta-analysis combining African American and European American T2D-ESKD data revealed P = 3.52 × 10(-7) and 3.70 × 10(-5) for rs9379084 and rs41302867 association, respectfully. A locus-wide analysis evaluating putatively functional SNPs revealed several nominal associations with T2D-ESKD, non-T2D-ESKD and T2D in African and European Americans. RREB1 is a large, complex gene which codes a multidomain zinc finger binding protein and transcription factor. We posit that variants in RREB1 modulate seemingly disparate phenotypes (i.e. T2D, T2D-ESKD and non-T2D-ESKD) through altered activity resulting from splice site and missense variants.

Topics: Aged; Alternative Splicing; Angiotensinogen; Black or African American; Case-Control Studies; Diabetes Mellitus, Type 2; DNA-Binding Proteins; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Haplotypes; Humans; Kidney Failure, Chronic; Male; Middle Aged; Mutation, Missense; Odds Ratio; Polymorphism, Single Nucleotide; Transcription Factors; White People

Heart Rate Variability (HRV) is extensively used to investigate general Autonomic Nervous System (ANS) function and is affected by many factors including age, gender, pathology such as diabetes and genetic polymorphisms. One of these genetic polymorphisms is the Angiotensin Converting Enzyme (ACE) polymorphism corresponding to insertion (I) or deletion (D) of a 287-base pair sequence of DNA in intron 16 of the ACE gene (rs4340). Some studies have addressed the relationship between HRV and D/D, I/D and I/I ACE polymorphism while others combined I/D and I/I ACE groups. In this study HRV is determined for diabetic and control individuals with different ACE polymorphism considering either separate or combined I/D and I/I genotypes. Linear time domain parameters, entropy, low frequency and total power of HRV were found to be significantly different between diabetic and control individuals with combined I/I and I/D ACE polymorphism, while only entropy was different for diabetic and control subjects with D/D ACE genotype. Separate analysis of I/I and I/D genotypes was preferred for a thorough investigation of HRV and ACE polymorphism, as the combined analysis masked some differences in HRV parameters such as Poincaré plot between ACE polymorphisms and diabetes status. Furthermore, a separate analysis demonstrated that most of the significant differences for HRV were between the diabetic group with I/I genotype and I/D and D/D groups.

Topics: Aged; Angiotensinogen; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Genetic Association Studies; Genotype; Heart Rate; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic

Patients with type 2 diabetes (T2D) are at high risk of developing hypertension and related cardiovascular disease. The renin-angiotensin system (RAS) plays a central role in regulation of blood pressure (BP). Accordingly, each component of this system represents a potential candidate in the etiology of hypertension. This study investigated the impact of polymorphisms within the RAS on ambulatory and central BP in T2D subjects. A cohort of 761 subjects (55-65 years) with T2D was studied. Ambulatory and central BP were measured, and ACE I/D genotype, angiotensinogen M235T, renin rs6693954 and ATR1-A1166C polymorphisms were analyzed. Women carrying the AA-genotype had lower 24-hour and day-time systolic and diastolic BP (p<0.05), and lower night-time and central diastolic BP (p<0.05), compared to T allele carriers. In men, the AA-genotype was instead associated with higher central diastolic BP (p=0.018) and higher augmentation index (p=0.016). Further, the associations between the renin rs6693954 SNP and diastolic BP were strongly gender dependent (p≤0.001). In T2D patients, there is a gender-dependent association of the renin rs6693954 SNP with central and ambulatory BP. Women carrying the renin rs6693954 AA-genotype may be protected against the higher BP seen in men with the same genotype.

Topics: Aged; Angiotensinogen; Blood Pressure; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System

Angiotensinogen (AGT) constitutes a central component of the renin-angiotensin system that controls the systemic blood pressure and several other cardiovascular functions and may play an important role in atherosclerosis pathways. In this study, we employed TaqMan genotyping assays to evaluate the role of 8 AGT variants in primary hypertension (HTN), type 2 diabetes mellitus (T2DM), and obesity as a possible trigger of coronary artery disease (CAD) in a population of 4615 angiographed native Saudi individuals.. Linkage analysis was done by using the Affymetrix Gene Chip array, sequencing by using the MegaBACE DNA analysis system and genotyping accomplished by TaqMan chemistry using the Applied Biosystem real-time Prism 7900HT Sequence Detection System.. Six variants, rs2067853 GG [Odds ratio(95% Confidence Interval) = 1.44(1.17-1.78); p = 0.001], rs7079 [1.49(1.20-1.85); p < 0.0001], rs699 G [1.19(1.08-1.13); p < 0.0001], rs3789679 A [1.51(1.14-1.99); p = 0.004], rs2148582 GG [1.31(1.11-1.55); p = 0.002] and rs5051 TC + CC [1.32(1.13-1.60); p = 0.001] conferred risk for HTN (3521 cases versus 1094 controls). The rs2067853 (p = 0.042), rs699G (p = 0.007) and rs5051 (p = 0.051) also conferred risk for myocardial infarction (MI; 2982 vs 1633), while rs3789679 A (p < 0.0001) and GA + AA (p < 0.0001) as well as rs4762G (p = 0.019) were associated with obesity (1576 vs 2458). However, while these variants appeared to be also associated with CAD (2323 vs 2292), only the rs7079G (p = 0.035) retained its significant relationship. Interestingly, among the haplotypes constructed from these SNPs, the baseline 8-mer haplotype, GGTGGGGT (χ² = 7.02; p = 0.0081) and another GGCGGAGT (χ² = 5.10; p = 0.024), together with several of their derivatives were associated with HTN. T2DM was associated with two 8-mer haplotypes, GGTAGGAC (χ2 = 5.66; p = 0.017) and ATTGAGAC (χ² = 5.93; p = 0.015), obesity with GGCGGAGT (χ² = 9.49; p = 0.0021) and MI was linked to ATTGGGAC (χ² = 6.68; p = 0.010) and GGTGGGAT (χ² = 4.25; p = 0.039). Furthermore, several causative haplotypes were also shared among the risk traits as well as with CAD.. These results point to AGT as independently conferring risk for various cardiovascular traits, and possibly interacting with these traits in events leading to atherosclerosis.

Topics: Angiotensinogen; Arabs; Case-Control Studies; Chi-Square Distribution; Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus, Type 2; DNA Mutational Analysis; Female; Gene Frequency; Genetic Linkage; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Logistic Models; Male; Middle Aged; Obesity; Odds Ratio; Oligonucleotide Array Sequence Analysis; Phenotype; Polymorphism, Single Nucleotide; Real-Time Polymerase Chain Reaction; Risk Assessment; Risk Factors; Saudi Arabia

It is unclear when angiotensin II receptor blockers (ARBs) produce their strongest antialbuminuric effect (AAE) in patients with diabetic nephropathy. ARBs produce stronger AAEs when urinary excretion of reactive oxygen species (ROS) and/or of angiotensinogen (AGT) is higher before treatment, although the relationship between ROS, AGT, and the urinary albumin-to-creatinine ratio (ACR) is unclear. We sought to define the relationship between ROS and ACR and establish the stage at which ARBs exert maximal AAEs.. Urinary ROS and AGT and the ACR were measured in 277 hypertensive type 2 diabetic patients before ARB treatment, and changes in the ACR were analyzed over 16 weeks.. Urinary AGT and ROS showed similar changes as the disease progressed, and the increase in ACR often observed in patients with lower ROS and AGT reflects the mild AAE produced by ARBs. ROS and AGT levels and the AAE were all highest in albuminuric patients (ACR = 30-1,000 mg/g creatinine), whereas normoalbuminuric patients (ACR < 30mg/g creatinine) displayed variable ROS values and AAEs. Glycemic control exerted a stronger AAE than ARBs in normoalbuminuric patients, whereas it had a weak AAE in most nephrotic (ACR ≥ 1,000 mg/g creatinine) patients, who had low basal ROS and AGT values. Lowering blood pressure was effective at all stages and appeared to promote an AAE, even in nephrotic patients.. ARBs produce a maximal AAE in albuminuric patients, and lowering blood pressure enhances the AAE in patients at all stages, including the nephrotic stage.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensinogen; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Female; Humans; Male; Middle Aged; Reactive Oxygen Species

Although recent studies have proven that renin-angiotensin system (RAS) blockades retard the progression of diabetic nephropathy, the detailed mechanisms of their reno-protective effects on the development of diabetic nephropathy remain uncertain. In rodent models, it has been reported that reactive oxygen species (ROS) are important for intrarenal angiotensinogen (AGT) augmentation in the progression of diabetic nephropathy. However, no direct evidence is available to demonstrate that AGT expression is enhanced in the kidneys of patients with diabetes. To examine whether the expression levels of ROS- and RAS-related factors in kidneys are increased with the progression of diabetic nephropathy, biopsied samples from 8 controls and 27 patients with type 2 diabetes were used. After the biopsy, these patients were diagnosed with minor glomerular abnormality or diabetes mellitus by clinical and pathological findings. The intensities of AGT, angiotensin II (Ang II), 4-hydroxy-2-nonenal (4-HNE), and heme oxygenase-1 (HO-1) were examined by fluorescence in situ hybridization and/or immunohistochemistry. Expression levels were greater in patients with diabetes than in control subjects. Moreover, the augmented intrarenal AGT mRNA expression paralleled renal dysfunction in patients with diabetes. These data suggest the importance of the activated oxidative stress/AGT/RAS axis in the pathogenesis of diabetic nephropathy.

Topics: Adult; Aldehydes; Angiotensinogen; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Heme Oxygenase-1; Humans; Kidney; Male; Oxidative Stress; Reactive Oxygen Species; Renin-Angiotensin System

We have previously reported that intrarenal angiotensin II (Ang II) levels are increased long before diabetes becomes apparent in obese Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of type 2 diabetes. In this study, we examined the changes in intrarenal renin-angiotensin system (RAS) activity in the developing kidneys of OLETF rats. Ang II contents and mRNA levels of RAS components were measured in male OLETF and control Long-Evans Tokushima (LETO) rats at postnatal days (PND) 1, 5, and 15, and at 4-30 weeks of age. In both LETO and OLETF rats, kidney Ang II levels peaked at PND 1, then decreased during the pre- and post-weaning periods. However, Ang II levels and gene expression of RAS components, including angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE), were not significantly different between LETO and OLETF rats. Intrarenal Ang IIcontents further decreased during puberty (from 7 to 11 weeks of age) in LETO rats, bur not in OLETF rats. At 11 weeks of age, kidney Ang II levels, urinary AGT excretion, and mRNA levels of AGT and renin were higher in OLETF rats than in LETO rats, while blood glucose levels were not significantly different between these groups of rats. These data indicate that continued intrarenal expression of Ang II during pubescence contributes to the increases in intrarenal Ang II levels in prediabetic OLETF rats, and is associated with increased intrarenal AGT and renin expression. Inappropriate activation of the intrarenal RAS in the prediabetic stage may facilitate the onset and development of diabetic nephropathy in later life.

Topics: Albuminuria; Angiotensin II; Angiotensinogen; Animals; Blood Glucose; Blood Pressure; Body Weight; Collagen; Connective Tissue Growth Factor; Creatinine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Female; Gene Expression Regulation; Kidney; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred OLETF; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Time Factors; Transforming Growth Factor beta

The aim of this study was to evaluate the association of urinary tubular markers, interleukin-18 (IL-18) and angiotensinogen with albuminuria in early nephropathy of type 2 diabetics.. Urine levels of tubular markers (kidney injury molecule [KIM]-1, neutrophil gelatinase-associated lipocalin [NGAL] and liver-type fatty acid-binding protein [L-FABP]), proinflammatory marker (IL-18), and a marker of intrarenal renin-angiotensin system (RAS) status (angiotensinogen) were determined in 118 patients with type 2 diabetes mellitus and 25 non-diabetic controls with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m(2).. Urinary levels of KIM-1, NGAL, IL-18 and angiotensinogen were significantly higher in macroalbuminuria group compared with control and normo- and microalbuminuria groups but not significantly different between control and normoalbuminuria group. Urinary tubular markers were positively correlated with urinary IL-18 and angiotensinogen, respectively. The urinary albuminuria was correlated with all investigated urinary markers in univariate analysis. After adjusting for several clinical parameters, urinary KIM-1, NGAL and angiotensinogen were significantly associated with albuminuria.. The results of this study suggest that urinary tubular markers may be independently associated with albuminuria in the early stage of nephropathy in type 2 diabetics (eGFR ≥ 60 mL/min/1.73 m(2)) and may reflect inflammatory processing and the activation of the intrarenal RAS.

Topics: Acute-Phase Proteins; Albuminuria; Angiotensinogen; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fatty Acid-Binding Proteins; Female; Glomerular Filtration Rate; Hepatitis A Virus Cellular Receptor 1; Humans; Interleukin-18; Kidney Tubules; Lipocalin-2; Lipocalins; Male; Membrane Glycoproteins; Middle Aged; Proto-Oncogene Proteins; Receptors, Virus; Risk Factors

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Clinical Trials Data Monitoring Committees; Congresses as Topic; Diabetes Mellitus, Type 2; Endpoint Determination; Fumarates; Heart Failure; Humans; Randomized Controlled Trials as Topic; Rats; Renin; Renin-Angiotensin System

The association between renin C-4063T and angiotensinogen (AGT) T174M, M235T, and A-6G polymorphisms with diabetic nephropathy (DN) was investigated in Tunisian type 2 diabetes (T2DM) patients.. Study subjects comprised 917 T2DM patients (405 normoalbuminuric, 329 microalbuminuric and 185 macroalbuminuric). Genotyping was done by PCR-RFLP.. Renin C-4063T allele and genotype frequencies were comparable between DN cases and normoalbuminuric controls. Although AGT 235T and -6G allele, and 235T/T and -6G/G genotype frequencies were higher in DN compared to normoalbuminuric patients, they were comparable between microalbuminuric or macroalbuminuric patients. Three-locus AGT haplotype analysis (A-6G/T174M/M235T) identified DN-protective (ATM, AMM, GTM) and DN-susceptible (GTM, ATT, GMT and AMT) haplotypes, and demonstrated enrichment of GTT haplotype in macroalbuminuric compared to microalbuminuric or normoalbuminuric patients. Regression analysis confirmed negative (AMM) and positive (GTM, ATT, GMT, AMT) association of AGT haplotypes with microalbuminuria, and negative (AMM) and positive (GTM and ATT) association of AGT haplotypes with macroalbuminuria. None of the AGT haplotypes was associated with DN severity.. Genetic variation at the AGT gene influences the risk of nephropathy in T2DM patients but not extent of DN severity, and thus represents a potential DN genetic susceptibility locus worthy of replication.

Topics: Angiotensinogen; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Middle Aged; Odds Ratio; Regression Analysis; Renin-Angiotensin System

Diabetic nephropathy (DN) is a leading cause of diabetes-related morbidity and mortality. The aim of this study was to evaluate the relationship of AGT M235T and apoprotein E (APO E) gene polymorphism with DN in Turkish patients of Type 2 diabetes, and to compare genotype and allele distributions among DN patients, non-DN patients, and healthy controls.. AGT M235T and APO E genotype and allele analysis were performed in 111 DN patients, 108 non-DN patients, 106 healthy control subjects for APO E genotype, and 100 for AGT M235T genotype polymorphism. APO E and AGT M235T genotype were determined by RFLP-PCR.. The frequencies of APO E ε2/3, ε 3/3, ε 3/4 genotypes were 22.7%, 60%, 60%, respectively, among DN patients and 6.6%, 80%, 10.4%, respectively (p < 0.001), in the non-DN patients. The frequencies of AGT M235T MM, MT, TT genotypes among the same groups were 17%, 46%, 37% and 21%, 63%, 16%, respectively (p < 0.02). Having the ε2/3 genotype and TT genotype increased the risk for DN nephropathy [4.8-fold (95% CI: 1.94-11.67), 2.9-fold (95% CI: 1.27-6.69), respectively].. Our study has shown that AGT M235T TT genotype and APO E ε 2/3 genotype may be linked to a risk for DN among Turkish population.

Topics: Aged; Alleles; Amino Acid Substitution; Angiotensinogen; Apolipoproteins E; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Turkey

Combination therapy of angiotensin-converting enzyme (ACE) inhibition and AT(1) receptor blockade has been shown to provide greater renoprotection than ACE inhibitor alone in human diabetic nephropathy, suggesting that ACE-independent pathways for ANG II formation are of major significance in disease progression. Studies were performed to determine the magnitude of intrarenal ACE-independent formation of ANG II in type II diabetes. Although renal cortical ACE protein activity [2.1 +/- 0.8 vs. 9.2 +/- 2.1 arbitrary fluorescence units (AFU) x mg(-1) x min(-1)] and intensity of immunohistochemical staining were significantly reduced and ACE2 protein activity (16.7 +/- 3.2 vs. 7.2 +/- 2.4 AFU x mg(-1) x min(-1)) and intensity elevated, kidney ANG I (113 +/- 24 vs. 110 +/- 45 fmol/g) and ANG II (1,017 +/- 165 vs. 788 +/- 99 fmol/g) levels were not different between diabetic and control mice. Afferent arteriole vasoconstriction due to conversion of ANG I to ANG II was similar in magnitude in kidneys of diabetic (-28 +/- 3% at 1 microM) and control (-23 +/- 3% at 1 microM) mice; a response completely inhibited by AT(1) receptor blockade. In control kidneys, afferent arteriole vasoconstriction produced by ANG I was significantly attenuated by ACE inhibition, but not by serine protease inhibition. In contrast, afferent arteriole vasoconstriction produced by intrarenal conversion of ANG I to ANG II was significantly attenuated by serine protease inhibition, but not by ACE inhibition in diabetic kidneys. In conclusion, there is a switch from ACE-dependent to serine protease-dependent ANG II formation in the type II diabetic kidney. Pharmacological targeting of these serine protease-dependent pathways may provide further protection from diabetic renal vascular disease.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Arterioles; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Kidney; Male; Mice; Mice, Mutant Strains; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Serine Proteases; Signal Transduction; Vasoconstriction

The genes encoding renin-angiotensin system (RAS) components are potent candidate genes in both hypertension and diabetes namely ACE encoding the angiotensin converting enzyme and AGT encoding angiotensinogen. It has been suggested that the insertion/deletion (I/D) polymorphism in intron 16 of ACE gene is associated with ACE levels, and M235T gene polymorphism is associated with plasma AGT levels.. We examined in this report the association between ACE I/D and AGT M235T polymorphisms with hypertension status in Tunisian type 2 diabetic subjects.. Thirty nine hypertensive and 22 normotensive type 2 diabetic Tunisian patients were recruited for this study. The I/D polymorphism of ACE gene was analysed with nested PCR in order to avoid mistyping heterozygous individuals and the M235T polymorphism of AGT gene was analysed using PCR and allele specific restriction.. The distribution of DD, ID and II genotypes did not significantly differ between type 2 diabetic patients with or without hypertension (DD: 49%; ID: 41%; II: 10% vs DD: 36%; ID: 55%; II: 9%, respectively) (chi2=1.06, p=0.58). There was also no significant statistical difference between these two groups for the M235T polymorphism (TT: 20%; MT: 54%; MM: 26% vs TT: 27%; MT: 41%; MM: 32%, respectively) (chi2=0.95, p=0.62).. RAS polymorphisms do not seem to play a role in the development of hypertension in the studied Tunisian type 2 diabetic subjects.

Topics: Aged; Algorithms; Angiotensinogen; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Renin-Angiotensin System; Tunisia

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.. One hundred and fourteen T2DM patients were compared to 175 healthy controls with similar age and sex.. 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.. 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.

Topics: Adult; Aged; Angiotensinogen; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Logistic Models; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors; Tunisia

The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a new model of obese type 2 diabetes, shows obesity, hyperglycemia, and hyperlipidemia from 6 weeks of age. Diabetic complications such as nephropathy and cataract are observed with aging; however, blood pressure change with age has not previously been examined. In this study, blood pressure was periodically measured and the change was investigated. Blood pressure in male SDT-fa/fa rats was elevated at 8, 16, and 24 weeks of age, whereas the heart rate was not changed. In addition to hyperglycemia, hyperlipidemia, and proteinuria, hyperleptinemia and increased urine angiotensinogen were observed in SDT-fa/fa rats. Blood pressure and heart rate in the male original SDT (SDT-+/+) rat did not significantly change. In conclusion, the SDT-fa/fa rat is a promising model, showing significant hypertension with diabetes mellitus.

Topics: Angiotensinogen; Animals; Blood Pressure; Diabetes Mellitus, Type 2; Disease Models, Animal; Heart Rate; Hyperglycemia; Hyperlipidemias; Hypertension; Leptin; Male; Obesity; Proteinuria; Rats; Rats, Sprague-Dawley

We investigated the gender differences in the effect of ACE I/D and AGT M235T polymorphisms on the prognosis of diabetic nephropathy (DN).. A total of 525 type 2 diabetics were enrolled to participate in this prospective observational study. ACE and AGT gene polymorphisms were analyzed by polymerase chain reaction. The progression of DN was defined as a shift to a higher stage of DN or a doubling of the baseline serum creatinine level by the end of the study.. The baseline biophysical parameters show no gender differences in progression and non-progression of DN. The women who were ACE D allele carriers were found to be at an increased risk of DN progression compared to those with II genotypes (p = 0.024, OR 2.176). No such difference was seen in male patients (p = 0.619, OR 0.833). After adjusting for confounding factors (age, SBP, DBP, BMI, HbA1c, total cholesterol, TG, HDL-C, LDL-C, ACEI, and ARB) in our multiple regression analysis, these women were still found to be at increased risk of progressing to more severe DN (p = 0.008, OR 3.082) but not the men (p = 0.183, OR 0.586). Neither the AGT TT genotype nor the T allele were associated with the progression of DN in either sex after adjusting for confounding factors.. Our follow-up study suggests that female diabetic carriers of the ACE D allele might be at an increased risk of DN progression.

Topics: Aged; Albuminuria; Angiotensinogen; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Female; Genotype; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Sex Characteristics; Sex Distribution; Taiwan

To study the combined effect of polymorphisms in genes of the renin-angiotensin system on mortality in type 2 diabetic patients in dialysis.. From 1993 to 2007, we followed 89 patients from the start of dialysis until the end point, which was all-cause mortality. All patients were genotyped for the following polymorphisms: ACE (I/D), AGT (p.235M>T) and AGTR1 (g.1166A>C). The relative risks of death were examined by Cox-proportional hazard analysis after adjusting for age, sex, modality of dialysis, baseline and residual filtration rate, cardiovascular comorbidity, anemia, glycemic control, hypertension, nutritional status, risk of infection and dyslipidemia.. We first assigned and quantified the number of risk alleles--D (I/D), M (p.235 M>T) and A (g.1166A>C)--each patient carried. The Cox-proportional hazard analysis showed that every single additional risk allele multiplied the mortality hazard ratio by 1.58 (95% CI: 1.16-2.15, P=0.003).. Our data suggest a combined effect among the polymorphisms of the Renin-Angiotensin-System genes on mortality in type 2 diabetic patients undergoing dialysis.

Topics: Aged; Angiotensinogen; Diabetes Mellitus, Type 2; Female; Humans; Male; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Proportional Hazards Models; Receptors, Angiotensin; Renal Dialysis; Renin-Angiotensin System

The renin-angiotensin aldosterone system (RAAS) plays an important role in regulating the blood pressure and the genetic polymorphisms of RAAS genes has been extensively studied in relation to the cardiovascular diseases in various populations with conflicting results. The aim of this study was to determine the association of five genetic polymorphisms (A6G and A20C of angiotensinogen (AGT), MboI of renin, Gly460Trp of aldosterone synthase and Lys173Arg of adducin) of RAAS genes in Malaysian essential hypertensive and type 2 diabetic subjects.. RAAS gene polymorphisms were determined using mutagenically separated PCR and PCR-RFLP method in a total of 270 subjects consisting of 70 hypertensive subjects without type 2 diabetes mellitus (T2DM), 60 T2DM, 65 hypertensive subjects with T2DM and 75 control subjects.. There was significant difference found in age, body mass index, systolic/diastolic blood pressure, fasting plasma glucose and high density lipoprotein cholesterol levels between the hypertensive subjects with or without T2DM and control subjects. No statistically significant differences between groups were found in the allele frequency and genotype distribution for A20C variant of AGT gene, MboI of renin, Gly460Trp of aldosterone and Lys173Arg of adducin (p > 0.05). However, the results for A6G of AGT gene revealed significant differences in allele and genotype frequencies in essential hypertension with or without T2DM (p < 0.001).. Among the five polymorphisms of RAAS genes only A6G variant of AGT gene was significantly associated in Malaysian essential hypertensive and type 2 diabetic subjects. Therefore, A6G polymorphism of the AGT gene could be a potential genetic marker for increased susceptibility to essential hypertension with or without T2DMin Malaysian subjects.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Cytochrome P-450 CYP11B2; Diabetes Mellitus, Type 2; Female; Genetic Markers; Genetic Predisposition to Disease; Humans; Hypertension; Malaysia; Male; Middle Aged; Polymorphism, Genetic; Renin-Angiotensin System

Variation in the renin-angiotensin system (RAS) and salt-sensitivity genes may influence the effect of thiazides on the risk of diabetes. We assessed whether polymorphisms in RAS and salt-sensitivity genes influenced the risk of diabetes associated with thiazides.. Nested case-control study was conducted among antihypertensive drug users. Pharmacy records and questionnaires were used to assess new onset diabetes (cases), to ascertain antihypertensive use and risk factors for diabetes. Cases were matched to controls (up to five) who were not (yet) diagnosed with diabetes mellitus. We genotyped angiotensin-converting enzyme (ACE) (G4656C), angiotensinogen (AGT) (M235T), angiotensin II type 1 receptor, (AGTR1) (A1166C), adducin 1 (alpha) (ADD1) (G460T), guanine nucleotide binding protein (G protein), beta-polypeptide 3 (GNB3) (C825T).. Among 497 incident cases of type 2 diabetes and 2,633 controls, AGTR1 CC genotype carriers had no increased risk of diabetes due to thiazides (odds ratio (OR) 0.63 (95% confidence interval (CI): 0.28-1.40)) compared to AGTR1 1166A allele carriers (OR 1.79 (95% CI: 1.43-2.23)) receiving thiazides (synergy index (SI) for interaction 0.32 (95% CI: 0.15-0.68)). Although homozygous ACE GG subjects and ACE C allele carriers both had an increased risk of diabetes associated with thiazide use, this risk was more increased for ACE GG subjects (SI 1.70 (95% CI: 1.08-2.66)), particularly at doses > or =1 daily defined dose (DDD) (=25 mg hydrochlorothiazide)/day (SI 2.0 (95% CI: 1.20-3.32)). Among GNB3 T allele carriers, the risk of diabetes due to thiazide use was less increased than among homozygous GNB3 CC subjects (SI 0.62 (95% CI: 0.41-0.93)).. The risk of diabetes due to thiazide use was not increased among AGTR1 1166 CC homozygous subjects and less increased among GNB3 T allele carriers. The ACE 4656 GG genotype enhanced the risk of diabetes due to thiazides.

Topics: Aged; Angiotensinogen; Calmodulin-Binding Proteins; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Heterotrimeric GTP-Binding Proteins; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk; Sodium Chloride Symporter Inhibitors

Increased activation of the renin-angiotensin system (RAS) may be important in promoting coronary heart disease (CHD) and renal dysfunction, but limited data are available on associations between angiotensin type 1 receptor (AGT1R) and angiotensinogen (AGT) genotypes in type 2 diabetes.. Study participants were diabetics from the Health Professionals Follow-Up Study (HPFS) and the Nurses' Health Study (NHS). We analyzed single nucleotide polymorphisms (SNPs) associated with cardiovascular pathophysiology (including AGT1R T573C, AGT1R A1166C, and AGT M235T) and presence of renal dysfunction (eGFR<60 ml/min/1.73 m2) or history of CHD.. The AGT1R 1166 C-allele was associated with eGFR<60 ml/min/1.73 m2 (multivariable OR 1.63 [1.01, 2.65]) in the HPFS men (n = 733) and in the combined dataset (n = 1566) (OR 1.42 [1.02, 1.98]). The AGT1R 1166 C-allele was also associated with CHD in men (OR 1.57 [1.10, 2.24]). In NHS women (n = 833), AGT 235T-allele was associated with CHD (OR 1.72 [1.20, 2.47]). Removal of hypertension from the fully adjusted models did not influence results, suggesting that the associations may not be mediated by hypertension. There were significant interactions between sex and AGT1R 1166 C-allele (p = 0.008) and AGT M235T (p = 0.03) in models for CHD. No significant associations were seen between AGT1R T573 C-allele and renal dysfunction or CHD.. Polymorphisms in AGT1R and AGT genes are associated with renal dysfunction and CHD in type 2 diabetes and further support the important role of the RAS in these complications. Sex may modify associations between AGT1R 1166 C-allele and AGT 235T and CHD in type 2 diabetes.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Angiotensinogen; Coronary Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Female; Follow-Up Studies; Gene Frequency; Genotype; Glomerular Filtration Rate; Health Personnel; Humans; Kidney Diseases; Male; Middle Aged; Mutation, Missense; Nurses; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk; Sex Factors

The aim of this study is to examine whether the ACE-I/D, AGT-M235T, and AT1R-A1166C polymorphisms of the renin-angiotensin system (RAS) genes are associated with cardiovascular and renal-related risk factors in Mexican Americans. Study participants (N = 848) were genotyped by Taqman assays. Association analyses were performed by measured genotype approach. Of the phenotypes examined, the ACE-I/D, AGT-M235T, and AT1R-A1166C polymorphisms exhibited significant association with systolic blood pressure, glomerular filtration rate and body mass index, respectively. The data suggest that the polymorphisms examined in the RAS may modulate the risk factors associated with cardiovascular-renal disease.

Topics: Albuminuria; Alleles; Angiotensinogen; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Variation; Genotype; Humans; Hypertension; INDEL Mutation; Kidney Diseases; Male; Mexican Americans; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors; Texas

Topics: Angiotensinogen; Apelin Receptors; Creatinine; Diabetes Mellitus, Type 2; Family; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Mexican Americans; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Texas

We recently reported that urinary excretion rates of angiotensinogen provide a specific index of the intrarenal renin-angiotensin system status in angiotensin II-dependent hypertensive rats. Angiotensinogen concentrations in mouse plasma are thought to be much lower than those in rat plasma; however, detailed information is deficient due to lack of direct quantitative measurements of rodent angiotensinogen. To elucidate this issue, we have developed a quantitative method for measurement of rodent angiotensinogen using a sandwich-type ELISA. The standard curve for mouse and rat angiotensinogen exhibited a high linearity at 0.16-10 and 0.08-5 ng/ml, respectively, with correlation coefficients >0.99. While plasma angiotensinogen concentrations of male high serum IgA (HIGA) mice (IgA nephritis model animals, 1,308 +/- 47 ng/ml; n = 10) were lower than those of control BALB/c mice (1,620 +/- 384; n = 12), urinary angiotensinogen concentrations of HIGA mice (14.6 +/- 1.5 ng/ml; n = 34) were higher than those of BALB/c mice (4.6 +/- 0.1; n = 2). In a similar manner, while plasma angiotensinogen concentrations of Zucker diabetic fatty (ZDF) obese rats (type 2 diabetic model animals, 1,789 +/- 50 ng/ml; n = 5) were lower than those of control ZDF lean rats (2,296 +/- 47; n = 5), urinary angiotensinogen concentrations of ZDF obese rats (88.2 +/- 11.4 ng/ml; n = 15) were higher than those of ZDF lean rats (31.3 +/- 1.9; n = 15). These data indicate that plasma and urinary angiotensinogen concentrations are less in mice than rats. However, these data suggest that urinary angiotensinogen levels are different from plasma angiotensinogen levels in rodents. The development of rodent angiotensinogen ELISA allows quantitative comparisons in mouse and rat angiotensinogen levels in models of hypertension and cardiovascular and kidney diseases.

Topics: Angiotensinogen; Animals; Antibody Specificity; Blotting, Western; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Genetic Vectors; Glomerulonephritis, IGA; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Obesity; Rats; Rats, Wistar; Rats, Zucker; Recombinant Proteins; Renin; Reproducibility of Results

1. The present study was performed to test the hypothesis that the reactive oxygen species (ROS)-angiotensinogen (AGT)-renin angiotensin system (RAS) axis is sequentially activated in the development of diabetic nephropathy in Zucker diabetic fatty (ZDF) obese rats. 2. Genetic pairs of male ZDF obese and control ZDF lean rats (n = 12 of each species) were killed every 3 weeks from 12 to 21 weeks of age (n = 6 at each time point). 3. The ZDF obese rats developed diabetes mellitus at 12 weeks. At that time, urinary excretion rates of 8-isoprostane were similar between the groups; however, urinary 8-isoprostane levels were significantly increased at 15 weeks in ZDF obese rats compared with controls (36 +/- 6 vs 15 +/- 2 ng/day, respectively). At 15 weeks, protein levels of cortical angiotensinogen were similar between groups; however, cortical angiotensinogen levels were significantly increased at 18 weeks in ZDF obese rats compared with controls (relative ratio of 2.32 +/- 0.21 vs 1.00 +/- 0.20, respectively). At 12 weeks, angiotensin (Ang) II-like immunoreactivity was similar between groups in both the glomeruli and tubules; however, AngII-like immunoreactivity was increased significantly at 21 weeks in ZDF obese rats compared with controls (relative ratios of 1.98 +/- 0.55 vs 1.00 +/- 0.03, respectively, for glomeruli and 1.58 +/- 0.16 vs 1.00 +/- 0.13, respectively, for tubules). Moreover, at 21 weeks, the desmin-positive area in the glomeruli (0.63 +/- 0.08 vs 0.22 +/- 0.05%) and Masson's trichrome stain-positive area in the interstitium (4.97 +/- 0.05 vs 3.18 +/- 0.41%) were significantly increased in ZDF obese rats compared with controls, even though these differences had not been observed earlier. 4. These data suggest that the sequential activation of the ROS-AGT-RAS axis plays an important role in the development of diabetic nephropathy in ZDF obese rats.

Topics: Angiotensinogen; Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Male; Obesity; Rats; Rats, Zucker; Reactive Oxygen Species; Renin-Angiotensin System; Time Factors

To elucidate the role of the renin-angiotensin system (RAS) in diabetic nephropathy, we examined the association between diabetic nephropathy in a large cohort of Japanese type 2 diabetic patients and polymorphisms within the genes that encode angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II receptor type 1 (AGTR1). Single nucleotide polymorphisms (SNPs) within these genes were genotyped using invader assay in 747 nephropathy cases and 557 control subjects. Eight SNPs within the ACE gene were significantly associated with diabetic nephropathy (P<0.05), including five SNPs in almost complete linkage disequilibrium to the insertion/deletion polymorphism in the 16th intron (P=0.01, odds ratio =1.34, 95% CI 1.07-1.69). Three SNPs within the AGT, including M235T and one SNP in the AGTR1, were also significantly associated with nephropathy (M235T P=0.01, odds ratio =0.74, 95% CI 0.59-0.94). In addition, we found that the allelic mRNA expression corresponding to the 235M allele was significantly higher than that for the 235T allele in normal kidney tissues. Furthermore, we found a significant additional effect of these three genes by a step-wise logistic regression analysis (final empirical P value =0.00005). We concluded that RAS gene polymorphisms may contribute to the susceptibility to diabetic nephropathy in type 2 diabetes.

Topics: Angiotensinogen; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Disease Susceptibility; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Because inhibition of the renin-angiotensin system (RAS) reduces the onset of type 2 diabetes (T2D) and prevents atherosclerosis, we investigated the expression of RAS in the arterial wall of T2D and nondiabetic (CTR) patients.. mRNA and protein levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and AT1 receptor (AT1R) were determined in carotid atheroma plaque, nearby macroscopically intact tissue (MIT), and in vascular smooth muscle cells (VSMCs) before and after insulin stimulation from 21 T2D and 22 CTR patients. AGT and ACE mRNA and their protein levels were 2- to 3-fold higher in atheroma and in MIT of T2D patients. VSMCs from T2D patients had respectively 2.5- and 5-fold higher AGT and AT1R mRNA and protein contents. Insulin induced an increase in AGT and AT1R mRNA with similar ED50. These responses were blocked by PD98059, an inhibitor of MAP-kinase in the two groups whereas wortmannin, an inhibitor of PI3-kinase, partially prevented the response in CTR patients. Phosphorylated ERK1-2 was 4-fold higher in MIT from T2D than from CTR patients.. The arterial RAS is upregulated in T2D patients, which can be partly explained by an hyperactivation of the ERK1-2 pathway by insulin.

Topics: Aged; Analysis of Variance; Angiotensinogen; Atherosclerosis; Biomarkers; Blotting, Western; Carotid Artery Diseases; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Gene Expression Regulation; Humans; Insulin; Male; Middle Aged; Probability; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Tissue Culture Techniques; Up-Regulation

Genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy and type II diabetes. To identify the genetic polymorphisms associated with diabetic nephropathy and type II diabetes, we performed a genome-wide association study using single-nucleotide polymorphisms as genetic markers. We also analyzed polymorphisms within the genes encoding for the renin-angiotensin system that were considered as candidate genes for diabetic nephropathy susceptibility and the transcription factor 7-like 2 (TCF7L2) as a candidate for type II diabetes, in a large cohort of a Japanese population. A genome-wide association study identified SLC12A3 and engulfment and cell motility 1 gene as the new candidates for diabetic nephropathy and transcription factor-activating protein 2beta as a novel susceptibility gene for type II diabetes; this observation was based on the significant association between the polymorphisms within the genes and the corresponding diseases (P<0.0001). Further, we discovered that the genes encoding the angiotensin-converting enzyme, angiotensinogen, and angiotensin II type I receptor have a significant combinational effect on conferring susceptibility to diabetic nephropathy. Furthermore, TCF7L2 that has been reported as a convincing susceptibility gene for type II diabetes in Caucasian populations was also shown to be associated with type II diabetes in a Japanese population. These genes could be considered as strong susceptibility genes for diabetic nephropathy and type II diabetes in the Japanese, although the new candidates that have been identified by genome-wide screening need to be examined in greater detail by several replication studies.

Topics: Angiotensinogen; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Genetic Predisposition to Disease; Genome, Human; Humans; Japan; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; TCF Transcription Factors; Transcription Factor 7-Like 2 Protein

Cardiovascular disease (CVD) is a major complication of Type 2 diabetes mellitus. The renin-angiotensin system (RAS) and nitric oxide production are both important regulators of vascular function and blood pressure. Genes encoding proteins involved in these pathways are candidates for a contribution to CVD in diabetic patients. We have investigated variants of the angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin type 1 receptor (AT1R) and endothelial nitric oxide synthase (NOS3) genes for association with subclinical measures of CVD in families with Type 2 diabetes mellitus (T2DM).. Atherosclerosis was measured by carotid intima-media thickness and calcification of the carotid and coronary arteries in 620 European Americans and 117 African Americans in the Diabetes Heart Study. Because of the role of these systems in blood pressure regulation, blood pressure was also investigated.. Compelling evidence of association was not detected with any of the SNPs with any outcome measures after adjustments for covariates despite sufficient power to detect relatively small differences in traits for specific genotype combinations.. Genetic variation of the RAS and NOS3 genes do not appear to strongly influence subclinical cardiovascular disease or blood pressure in this diabetic population.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Atherosclerosis; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium; Family Health; Female; Gene Frequency; Humans; Male; Middle Aged; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors

The role of interaction of polymorphisms in the Renin-Angiotensin-System (RAS) with angiotensin converting enzyme (ACE) or angiotensin receptor (AGTR1) inhibitors (RAS inhibitors) is unknown, as is the role of such therapy in end stage renal disease (ESRD) patients.. We enrolled all 445 prevalent patients with diabetic nephropathy receiving maintenance hemodialysis in 30 centers in Southern Germany from August 1999 to January 2000 for prospective survival analysis until December 2003. Blood pressure and medication was recorded at inclusion. We determined survival specific for allelic variants of the ACE (insertion/deletion), Angiotensinogen (M235T) and AGTR1 (A1166C) genes. The effect of therapy with RAS inhibitors at study inclusion was determined for the allelic variants of each gene. The primary end point was all cause mortality (ACM).. For all polymorphisms, and for therapy with RAS inhibitors there was no significant effect on survival in the complete collective (n = 445), though there was an insignificant trend for improved survival in patients on AGTR1 antagonists. Increased ACM risk was associated with treatment with RAS inhibitors only in patients homozygous for the wild type AGTR1 1166A allele (HR 1.65, p = 0.01). For all other polymorphisms, therapy with RAS inhibitors had no significant effect on ACM, irrespective of genotype. Similar results were obtained in patients with systolic ventricular dysfunction.. Our data do not show a survival advantage for type 2 diabetes hemodialysis patients receiving RAS inhibiting therapy. In addition, our data indicate that allelic variation in RAS genes and pharmacogenetic interaction with RAS inhibition does not affect mortality risk in diabetic hemodialysis patients.

Topics: Aged; Alleles; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Chronic Disease; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Genetic Variation; Genotype; Humans; Male; Peptidyl-Dipeptidase A; Prospective Studies; Receptor, Angiotensin, Type 1; Renal Dialysis; Renin-Angiotensin System; Survival Rate; Treatment Outcome

Topics: Amino Acid Substitution; Angiotensinogen; Asian People; China; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

This study compared the polymorphisms of angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1R) gene between type II diabetes with diabetic nephropathy (DN) in end-stage renal disease (ESRD) and those of the normal individuals in Taiwan.. 129 patients with type II diabetes in ESRD from three dialysis centers were compared to 116 age and blood pressure-matched normal individuals. Polymerase chain reaction (PCR) specific for ACE gene was tested for insertion/deletion polymorphism. M235T and T174M variant polymorphisms of the AGT gene and the AT1R A1166C polymorphism were also tested according to previously described protocols.. Between the two groups, frequencies of the alleles and the genotypes in ACE gene polymorphism were comparable. There was no significant difference of the ACE insertion and deletion polymorphism and AT1R gene polymorphism between the two groups. The allele frequencies of AGT point mutation at 235 (M235T) was significantly higher in DM nephropathy but the genotypic frequencies were not. In the AGT point mutation at 174 (T174M), the frequencies of both of alleles and genotypes were significantly higher in the DM nephropathy patients.. In conclusion, there were significantly higher frequencies of alleles and genotypes in AGT point mutation at 174, which had never been reported before. In AGT point mutation at 235, there were significantly higher frequencies of alleles, but not genotypes in diabetic nephropathy. Our study suggested that the AGT gene plays an important role in diabetic nephropathy.

Topics: Adult; Aged; Angiotensinogen; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin

To investigate the relationship between angiotensinogen (AGT) gene polymorphism and hypertension in type 2 diabetic patients.. A total of 240 patients with type 2 diabetes mellitus were divided into normotensive and hypertensive groups according to their blood pressure measurement, and their fasting plasma glucose, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein and very-low-density lipoprotein were measured. The AGT genotypes were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).. The distributions of AGT genotypes in normotensive and hypertensive groups were similar, and the frequency of M allele in female hypertensive patients was significantly higher than that in female normotensive patients.. The M allele of AGT gene is probably related to hypertension in female type 2 diabetic patients.

Topics: Adult; Aged; Angiotensinogen; Diabetes Mellitus, Type 2; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic

Conventional and genetic risk factors have been reported to play a role in the pathogenesis of vascular disease, but do not explain the lower burden of cardiac and peripheral vascular disease (PVD) in Chinese compared with Caucasians. The role of renin-angiotensin system (RAS) gene polymorphisms and conventional vascular risk factors has not been determined.. A total of 3097 Chinese diabetic subjects were screened for PVD, which was identified in 194 of the 2967 patients with Type 2 diabetes. Biochemical parameters and the genotype and allele frequencies of three RAS gene polymorphisms, the angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T and angiotensin II type 1 receptor (AT1R) A1166C polymorphisms were then compared between the PVD patients and 1046 age, gender and diabetes duration-matched patients without PVD.. PVD identified in 6.5% was associated with significantly worse glycaemic control, lipid profile and renal function. Smoking was more common, as were the other macro- and microvascular diseases. The prevalence of hypertension was similar between the groups, yet diastolic blood pressure was slightly lower in the PVD group. The ACE D allele was significantly more frequent in patients with PVD compared with the matched diabetic controls (38.1 vs. 29.8%, P = 0.039). No differences in the AT1R or AGT polymorphisms were observed.. PVD was associated with a worse metabolic profile and greater concomitant vascular disease than controls. The ACE I/D polymorphism was associated with PVD in these Type 2 diabetic patients.

Topics: Aged; Albumins; Angiotensinogen; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Creatinine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Gene Deletion; Gene Frequency; Genotype; Hong Kong; Humans; Male; Peptidyl-Dipeptidase A; Peripheral Vascular Diseases; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Triglycerides

Conflicting results on the relationship between M235T polymorphism of angiotensinogen (AGT) gene and diabetic nephropathy are reported in the literature, probably due to the small number of subjects, to different inclusion criteria and the different genotype analysis methods used. The aim of the present study was to set up a fast, cheap and reliable method to allow the genotyping of M235T polymorphism in a large number of subjects.. We developed in our laboratory a new specifically designed PCR-SSCP method for M235T genotyping whose specificity was compared with that of Allele Specific PCR (ASPCR) and Mutagenically Separated PCR (MS-PCR). The exact M235T genotype was estabilished by direct sequencing. The new PCR-SSCP method was then used to genotype a population of 1171 hypertensive, normoalbuminuric type II diabetes mellitus patients. The patients were also genotyped for ACE I/D polymorphism. For comparison a group of hypertensive non diabetic patients (n = 88) were also screened.. The PCR-SSCP method identified the M235T polymorphism with no misinterpretation at variance with ASPCR and MS-PCR methods that showed a preferential amplification of the T allele. The rare Y248C polymorphism of the AGT gene was also detected by PCR-SSCP. In diabetic hypertensive patients the prevalence of TT genotype was higher than in normotensive healthy controls and equivalent to that found in hypertensive non diabetic patients.. The PCR-SSCP method for detection of M235T polymorphism is a powerful and sensitive tool for rapid, cheap and efficient screening of a large number of samples. The results obtained with this method demonstrate an association of the TT genotype of AGT gene with hypertension, both in diabetic and non diabetic patients.

Topics: Adult; Aged; Alleles; Angiotensinogen; Base Sequence; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Genetic Testing; Genotype; Humans; Hypertension; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Reproducibility of Results; Sample Size; Sensitivity and Specificity; Time Factors

Diabetic nephropathy is the most frequent cause of end-stage renal failure. One of the crucial factors in a development of renal and cardiovascular complications of diabetes is genetic predisposition. The genes of the renin-angiotensin system are important group of candidate genes involved in pathogenesis of chronic renal diseases. The purpose of our study was the evaluation of a possible role of genetic polymorphisms of some of the RAS system genes in the nephropathy in type 2 diabetes. The study was performed in 117 patients with diabetic nephropathy, compared with 200 healthy subjects as a control group. The following polymorphisms: insertion/deletion (I/D) of the angiotensin-converting enzyme gene (ACE), M235T of the angiotensinogen gene (AGT) and A1166C of the angiotensin II type 1 receptor gene (AT1R) were evaluated by polymerase chain reaction (PCR). No statistically significant differences between groups were found in the allele frequency and genotype distribution for ACE and AGT polymorphisms. The results for the AT1R gene polymorphism revealed significant differences in allele and genotype frequencies. The homozygous CC genotype was more frequent in patients with diabetic nephropathy than in control group. Both genotypes with the C allele (AC + CC) were found in 56% of patients compared to 38% in control group. These results suggest increased susceptibility to diabetic nephropathy in individuals carrying the CC genotype. Therefore, the A1166C polymorphism of the AT1R gene could be a potential genetic marker for increased susceptibility to renal complications in type 2 diabetes.

Topics: Adult; Alanine; Alleles; Angiotensinogen; Case-Control Studies; Cysteine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Genotype; Humans; Male; Methionine; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System; Threonine

Albuminuria predicts nephropathy-related mortality in Caucasian and Chinese populations. The involvement of renin-angiotensin system (RAS) gene polymorphisms in the pathogenesis of nephropathy has been described predominantly in Caucasian populations. We have previously suggested that the angiotensinogen 235T variant may be associated with nephropathy in diabetic Chinese.. To validate these findings and extend them to include non-diabetic nephropathy, we examined the association of albuminuria and gene polymorphisms of the angiotensinogen M235T, angiotensin-converting enzyme insertion/deletion and angiotensin II type I receptor A1166C polymorphisms in 614 Chinese subjects (66% type 2 diabetic, 16% normoglycemic hypertensives and 18% controls).. Obesity and higher blood pressure were associated with albuminuria in both diabetes and normoglycemic hypertension. In the diabetic group, albuminuria was also associated with increased insulin resistance and glycemic indices, duration of diabetes and adverse lipid profiles. Only the ACE gene polymorphism showed evidence of association with albuminuria, with the D allele being less frequent in the normoglycemic hypertensive patients with albuminuria (25.0%) than the controls (41.4%) or normoalbuminuric group (39.6%) and in those hypertensives at increased risk (albumin-to-creatinine ratio > 5.6 mg/mmol) of end-stage renal disease than those at lower risk (all p < 0.05), but not in the diabetic group. The D allele was also less prevalent in the total (31.9%) and normoalbuminuric (32.2%) diabetic groups than in the controls (p < 0.05).. In this cohort of Chinese subjects, the ACE gene polymorphism D allele was less frequent in normoglycemic hypertensive patients with albuminuria and in type 2 diabetes.

Topics: Adult; Albuminuria; Angiotensinogen; Blood Glucose; China; Diabetes Mellitus, Type 2; Female; Gene Frequency; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Angiotensin; Renin-Angiotensin System

In Chinese populations, hypertension is common and is a major risk factor for cerebrovascular and coronary heart disease, particularly when associated with diabetes. The clustering of these disorders and dyslipidemia and obesity is termed the metabolic syndrome and is increasing in prevalence in the populations of modernizing Asian nations. The renin-angiotensin system (RAS) helps maintain blood pressure and salt homeostasis and may play a role in the pathogenesis of aspects of the metabolic syndrome. We investigated three RAS gene polymorphisms--the ACE insertion/deletion (I/D), angiotensinogen (AGT) M235T, and angiotensin II type 1 receptor (AT1R) A1166C polymorphisms--for a possible role in modulating these disorders in 853 Chinese subjects with varying components of the metabolic syndrome.. The three gene polymorphisms of this cross-sectional study were detected using polymerase chain reaction-based protocols. The genotype frequencies were compared between the controls (n = 119) and both overlapping and nonoverlapping groups of patients with type 2 diabetes, hypertension, and dyslipidemia using chi2 test. Differences in levels of the biochemical parameters between the genotypes were determined using analysis of variance.. No significant relationship was identified between these polymorphisms and blood pressure in this population. Although the AT1RA1166C polymorphism was not associated with any aspect of the metabolic syndrome examined, there was limited evidence to suggest that the AGT M235T polymorphism may be associated with cholesterol levels. The ACE I allele was significantly more frequent in each group comprising subjects with type 2 diabetes/glucose intolerance (GIT), and the I allele was associated with higher fasting plasma glucose levels.. These findings suggest that these polymorphisms are unlikely to be involved in the pathogenesis of hypertension. The ACE I/D polymorphism was associated with the metabolic syndrome, having a higher frequency of I allele-containing genotypes in those groups, but this appeared to result predominantly from the relationship with type 2 diabetes/GIT in this population of Chinese subjects.

Topics: Adult; Alleles; Angiotensinogen; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Gene Deletion; Genotype; Glucose Intolerance; Hong Kong; Humans; Hyperlipidemias; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System

The renin-angiotensin system is important in the control of hemodynamic status and pathogenesis of macrovascular disease, which is a major cause of morbidity and mortality in patients with type 2 diabetes with nephropathy. Serum angiotensin-converting enzyme (ACE) and angiotensinogen (Atg) levels are related to their respective gene polymorphisms. Seventy patients with type 2 diabetes with overt nephropathy (serum creatinine >/= 1.5 mg/dL) were studied. Serum ACE activity was measured by the spectrophotometric method. ACE deletion/insertion (D/I) and Atg M235T genotypes were determined by polymerase chain reaction. Patients with and without macroangiopathy were compared. Those with macroangiopathy had increased ACE activity (median, 60.9 U/L; range, 37.9 to 100 U/L versus without macroangiopathy, 47.9 U/L; range, 11.2 to 84.5 U/L; P = 0.01) and prevalence of ACE DD/DI genotypes (DD/DI:II: with macroangiopathy, 61%:39% versus without macroangiopathy, 34%:66%; P = 0.03). Multivariate analysis using age; sex; duration of diabetes; glycemic, blood pressure, and lipid level control; serum creatinine level; and presence of the ACE D allele showed that presence of the D allele (P = 0.03; odds ratio, 1.8; confidence interval, 1.1 to 3.1) and serum creatinine level (P = 0.0007) were independent risk factors for macroangiopathy. Association of the D allele became insignificant after serum ACE activity was included in the analysis in which only serum ACE activity (P = 0.004) and serum creatinine level (P = 0.01) were independent risk factors. Neither Atg M235T nor its synergistic effect with the ACE D allele showed an association with macroangiopathy. In conclusion, the ACE D allele is associated with macroangiopathy in Chinese patients with type 2 diabetes with nephropathy. The association is dependent on its effect on serum ACE activity, which is an independent risk factor for the development of macroangiopathy.

Topics: Aged; Alleles; Amino Acid Substitution; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Female; Gene Frequency; Genotype; Humans; Male; Middle Aged; Multivariate Analysis; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prospective Studies; Renin-Angiotensin System; Risk Factors

To investigate the relationship between angiotensin type I receptor (AGT I R) gene polymorphism and diabetic nephropathy (DN) and its progression.. PCR technique was used to determine the AGT I R gene polymorphism in 86 patients without DN, 67 with microalbuminuria, 66 with clinical albuminuria and 20 type 2 DM patients with renal insufficiency.. In comparing the DN group with the non-DN group, it was found that there was a significant difference of the frequency of AC genotype with DN (chi(2) = 4.30, P < 0.05), and C mutative type was more frequent in the DN group (chi(2) = 3.97, P < 0.05). No significant difference of AGTIR-A1166-C genotype was found in cases with different durations of DN.. Delete polymorphism of A1166-C gene is associated with DN in type 2 diabetes mellitus. It is suggested that detection of significant AGTIR-A1166-C polymorphism is of help for preventing DN in type 2 diabetes mellitus.

Topics: Adult; Aged; Angiotensinogen; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Genetic Variation; Humans; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Receptors, Angiotensin

Several studies have suggested that the same genetic factors may be involved in the predisposition to both essential hypertension and diabetic nephropathy, but the molecular mechanism underlying this predisposition still remains unclear. In particular, the role of genes involved in blood-pressure regulation and angiotensin II action is still controversial. This study examines a possible association between angiotensinogen M235T and chymase gene CMA/B polymorphisms with the presence of nephropathy in type II diabetic Caucasians.. For the purposes of the study, 323 microalbuminuric and 127 overt proteinuric cases, together with 243 normoalbuminuric controls with long-duration diabetes were selected from a group of 941 type II diabetic patients with established renal status.. No differences in the genotype distributions or allele frequencies of the examined polymorphisms between the study groups were observed. The study groups were also stratified by gender, diabetes duration, level of glycaemic control, body mass index, hypertension, and retinopathy status, but still no distortion in the distributions of genotypes of any of the examined polymorphisms in any of the strata was shown.. Our study provided evidence against an association between angiotensinogen M235T or chymase gene CMA/B polymorphisms and the presence of incipient or overt nephropathy in Caucasian patients with type II diabetes.

Topics: Aged; Angiotensinogen; Chymases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Serine Endopeptidases

Polymorphisms of angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) genes have been reported to be associated with myocardial infarction and coronary artery disease, both of which are closely related to atherosclerosis and insulin resistance. In this study, we investigated the association between ACE and AGT genotypes and insulin sensitivity in a sample of 142 nondiabetic and 64 noninsulin-dependent diabetes mellitus (NIDDM) Japanese subjects, aged 62.7 +/- 9.5 years. The insulin response to the 75-g oral glucose tolerance test (OGTT) was significantly lower in subjects with the ACE D/D genotype compared to those with the I allele (I/D and I/I genotypes) in both nondiabetic (P < 0.05) and NIDDM subjects (P < 0.005). These homozygous D/D subjects also had lower insulin area under the curve of plasma insulin concentrations during OGTT compared to those with the I allele in nondiabetic (P < 0.05) and NIDDM subjects (P < 0.01). However, there was no significant association between AGT genotypes and either insulin response or insulin area under the curve during OGTT, in either nondiabetic or NIDDM subjects. From a viewpoint that insulin response to oral glucose is significantly correlated with insulin sensitivity, these results suggest that polymorphic variations at the ACE gene, but not the AGT gene, may be involved in the genetic regulation of insulin sensitivity in both nondiabetic and NIDDM Japanese subjects.

Topics: Aged; Alleles; Angiotensinogen; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 2; DNA Primers; Female; Genotype; Glucose Tolerance Test; Humans; Insulin; Japan; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic

The prevalence of diabetic nephropathy is greater in nonwhite patients with type II diabetes, including the Chinese, and genetic variation appears to have a role. We examined angiotensin-converting enzyme (ACE) DD/II and angiotensinogen (Atg) M235T polymorphism in a cohort of Chinese patients with type II diabetes with an average duration of diabetes of 14 years. Group A (n = 88) did not have significant diabetic nephropathy (creatinine levels 130 micromol/L [>1.48 mg/d], and those undergoing dialysis). The two groups were matched in different aspects, including age, duration of diabetes, blood pressure, and glycemic control. The results showed: (1) no difference of genotype distribution between groups A and B (DD:DI:II, 14%:45%:41% v 8%:38%:54%; P = 0.20; TT:TM/MM, 70%:30% v 76%:24%; P = 0.43), (2) no evidence of synergistic effect of ACE (DD/II) and Atg M235T gene polymorphisms, (3) no difference of allele frequencies between groups A and B (D:I, 36%:64% v 27%:73%; P = 0.20 and T:M, 86%:16% v 86%:14%; P = 0.73), and (4) ACE activity was greatest in patients with DD genotype and least in those with II genotype (DD:DI:II = 66. 9 +/- 13.3 U/L:61.5 +/- 19.9 U/L:45.0 +/- 17.0 U/L; P < 0.005). The data do not support a role of ACE (DD/II) or Atg M235T polymorphism in the development of diabetic nephropathy in Chinese patients with type II diabetes, and no synergistic effect was found between them. Greater ACE activity was associated with DD genotype, and its role in diabetic nephropathy remains to be elucidated.

Topics: Aged; Angiotensinogen; Asian People; China; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic

To assess the association between the common variation in the gene encoding angiotensinogen, AGT, and the presence of microalbuminuria in Canadian Oji-Cree with type 2 diabetes mellitus.. We compared the frequencies of the AGT promoter and M235T polymorphisms among three subgroups of adult Oji-Cree: 50 subjects who had type 2 diabetes with microalbuminuria, 6 subjects who had type 2 diabetes without albuminuria and 302 non-diabetic, normotensive subjects.. We found the AGT T235 allele was present at a significantly higher frequency, and that T235/T235 homozygotes were significantly more prevalent, among the subjects who had type 2 diabetes with microalbuminuria than among the subjects in the other two groups.. The findings suggest that the AGT T235 allele is a determinant of the nephropathy susceptibility related to type 2 diabetes in these aboriginal Canadians.

Topics: Adolescent; Adult; Albuminuria; Angiotensinogen; Diabetes Mellitus, Type 2; Female; Gene Frequency; Humans; Indians, North American; Male; Middle Aged; Polymorphism, Genetic

To investigate whether angiotensinogen(AGT) gene M235T variant is associated with type 2 diabetes mellitus without nephropathy (DM) and/or diabetic nephropathy (DN) in Chinese type 2 diabetes.. AGT genotypes of 84 cases with DM, 96 with DN and 98 controls were determined by polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism analysis of the region of the variant.. Increased frequencies of T allele (0.82) and TT genotype (0.70) were observed in 96 subjects with DN, compared with those observed in 98 control subjects (0.63 and 0. 43 respectively, P = 0.003, P = 0.0004). The odds ratio associated with TT genotype was 3.47 (95% CI 1.51-7.94, P = 0.0033) for DN in analysis adjusted for several DN risk factors. There was no difference in allele distribution between 84 DM patients and the controls.. TT genotype of the AGT gene might be an independent risk factor of diabetic nephropathy in Chinese patients with type 2 diabetes mellitus.

Topics: Adult; Aged; Angiotensinogen; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Genetic Variation; Genotype; Humans; Male; Middle Aged; Risk Factors

To clarify risk factors for the progression of microalbuminuria in Japanese type 2 diabetic patients, the longitudinal study for 10 years was conducted on 67 outpatients with type 2 diabetes, who had shown no overt proteinuria at baseline. The urinary albumin index (UAI) has been determined based on the mean of at least two random urine samples each year. Categories were defined as normoalbuminuria (UAI < 30.0 mg/g x Cr.), microalbuminuria (30.0 < or = UAI < 300.0), and macroalbuminuria (UAI > or = 300.0). Progression was defined as worsening of the category and/or more than doubling of the baseline UAI value. Multiple logistic regression analysis was performed using age, duration of diabetes, HbA1c, blood pressure, BMI, serum lipids, smoking habits, and alcohol consumption as independent variables and the progression of microalbuminuria as a dependent variable. Age and HbA1c were estimated as significant and independent variables. Furthermore, genetic polymorphisms of angiotensin I-converting enzyme (ACE) and angiotensinogen were analyzed to evaluate the genetic contribution. The D/D genotype of ACE was significantly more common in progressors than in non-progressors. These results suggest that glycemic control and age are important risk factors and the D/D genotype of ACE acts as a risk factor for the progression of microalbuminuria in Japanese type 2 diabetic patients.

Topics: Adult; Aged; Albuminuria; Angiotensinogen; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Disease Progression; Genotype; Humans; Hypertension; Japan; Longitudinal Studies; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors

Familial clustering of altered albumin excretion and nephropathy risk has been described in both type 1 and type 2 diabetes; moreover, an association of micro-macroalbuminuria and diabetic retinopathy has been recently reported in a large number of white families with type 2 diabetes. Conflicting reports, mainly comparing affected with unaffected unrelated subjects, have suggested a possible role of some genotypes of the renin-angiotensin system in conferring nephropathy risk in type 2 diabetes. To examine the role of genetic factors in influencing albuminuria in families, we studied the relation of angiotensin-converting enzymes (ACE) and angiotensinogen (AGN) genotypes with albumin excretion rate in a population of affected siblings of type 2 diabetic probands. We determined ACE insertion/deletion polymorphism and two polymorphisms of the AGN gene (T174M and M235T) in 160 families with at least one affected member. Defining proband as the patient with the longest known duration of diabetes, we compared the allelic distribution in diabetic probands with and without altered albumin excretion and in their siblings. Allelic distribution of these polymorphisms was similar in the two groups of probands, as well as in their siblings. Identity-by-State (IBS) analysis showed a link between AGN locus and arterial hypertension in these siblings, which was independent from the degree of renal involvement. Thus, our findings suggest that in white families with type 2 diabetes, there is no linkage between the degree of albumin excretion and ACE and AGN polymorphisms, whereas the latter is related to arterial hypertension, as previously found in patients without diabetes but with essential hypertension.

Topics: Albuminuria; Alleles; Angiotensinogen; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Genetic Linkage; Genotype; Humans; Hypertension; Italy; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic

To study the association between polymorphisms in the angiotensin converting enzyme (ACE) gene and angiotensinogen (AGT) gene and hypertension and/or type 2 diabetes in a community population.. The insertion (I)/deletion (D) polymorphism of the ACE gene and the M235T polymorphism of the AGT gene were genotyped in 773 nondiabetic individuals with hypertension, 193 normotensive patients with type 2 diabetes, 243 patients with type 2 diabetes and hypertension, and in 820 normotensive control individuals identified in a community-based study.. The DD genotype was associated with hypertension in individuals less than 70 years [odds ratio (OR) = 1.54, confidence interval (CI) = 1.09-2.18] and remained so when patients with type 2 diabetes were excluded from the analysis (OR = 1.45, CI = 1.01-2.09). The strongest association was with the combination of type 2 diabetes and hypertension (OR = 2.19, CI = 1.09-4.38). There was no association with type 2 diabetes without hypertension. No association was observed between the M235T variant or the 3'-microsatellite polymorphism of the AGT gene and hypertension.. The D-allele of the ACE gene ID polymorphism increases susceptibility to hypertension, particularly when associated with type 2 diabetes. No association was observed between the M235T variant or 3'-microsatellite polymorphism of the AGT gene and hypertension.

Topics: Aged; Aging; Angiotensinogen; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic

To investigate whether angiotensinogen (AGT) gene M235T variant is associated with non-insulin-dependent diabetes mellitus without nephropathy (DN-), and diabetic nephropathy (DN+) in Chinese non-insulin-dependent diabetes mellitus (NIDDM).. The subjects in DN+ group, DN- group and control group were well matched with sex, age and duration of disease, and the two case groups were divided into two subgroups as with and without hypertension respectively. The M235T polymorphism of AGT gene of 84 cases with DN-, 96 patients with DN+ and 98 controls were determined by polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism (RFLP) analysis of the region of the variant, i.e. M235T polymorphism.. The increased frequencies of T allele (0.82) and TT genotype (0.70) were observed in 96 subjects with DN+ as compared with 98 control subjects (0.63 and 0.43, respectively, P = 0.003, P = 0.0004). The odds ratio associated with TT genotype was 3.47 (95% CI: 1.51-7.94; P = 0.0033) for diabetic nephropathy in analysis adjusted for several risk factors of diabetic nephropathy, such as body-mass index, systolic and diastolic blood pressure, serum cholesterol, low density lipoprotein and high density lipoprotein. Subgroup analysis of the 67 patients in DN+ group with hypertension revealed similar distributions of M235T genotypes and alleles to those in the DN+ without hypertension subgroup. There was no difference in allele and genotype distribution between 84 DN- patients and the controls. Similarly, frequencies of the AGT M235T genotype and allele were not different between two DN- subgroups.. AGT gene M235T polymorphism is associated with diabetic nephropathy in NIDDM. TT genotype of the AGT gene might be an independent risk factor of diabetic nephropathy in Chinese NIDDM patients.

Topics: Adult; Aged; Angiotensinogen; Asian People; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Genetic Variation; Genotype; Humans; Male; Middle Aged; Polymorphism, Restriction Fragment Length; Risk Factors

This study examined the association between the development of nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) patients and M235T polymorphism in the angiotensinogen gene. White NIDDM patients with diabetic nephropathy (case subjects, n = 117) and patients without any evidence of nephropathy and > or = 10 years of NIDDM (control subjects, n = 125) were selected from among patients of the Joslin Diabetes Center and examined. In addition to a standardized examination, blood was drawn for DNA and determination of M235T genotypes at the angiotensinogen locus. For the angiotensinogen gene, the frequency of the genotype 235T/235T, known to be associated with essential hypertension, was higher among case subjects with nephropathy than in control subjects without this complication. This difference, expressed as the odds ratio for nephropathy among 235T/235T homozygotes in comparison with all other genotypes, was 2.2 (95% confidence interval, 1.1 to 4.4). The difference, however, was confined to men (odds ratio, 4.8; 95% confidence interval, 1.5 to 14.9), with the distribution of genotypes in case and control subjects being equal among women (odds ratio, 1.1). DNA polymorphism M235T in the angiotensinogen gene, which is associated with higher expression of this gene, contributes to the risk of diabetic nephropathy in NIDDM men but not in women.

Topics: Adult; Angiotensinogen; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Gene Frequency; Genotype; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Odds Ratio; Point Mutation; Polymorphism, Genetic; Sex Factors

Genetic polymorphisms of the renin-angiotensin system (RAS) have been implicated in the pathogenesis of diabetic proteinuria. Ethnic differences in the frequencies of these genotypes have also been reported. To date, most of these studies have been performed in white and Japanese populations. In this study, we examined the associations between albuminuria and RAS genetic polymorphisms in Chinese patients with type 2 diabetes.. In a case-control study, the ACE insertion/deletion (I/D) gene, the angiotensinogen (AGT) gene (M235T), and the angiotensin II (AII) type 1 receptor gene (AT1 A1166C) were examined in 110 Chinese type 2 diabetic patients. Increased urinary albumin excretion (UAE) was defined as > or = 30 mg/day on at least two occasions during a 6-week study period.. Compared with whites, there were high frequencies of the AGT TT genotype in Chinese control subjects (120/183 = 70%) and type 2 diabetic patients (74/110 = 67%). The frequencies of the MM genotype were 5 and 3%, respectively, and those of the ACE DD genotype were 13 and 10%, respectively. Although 9% of subjects carried the C allele, the AT1 CC genotype was not found in either group. Chinese type 2 diabetic patients with increased albuminuria (n = 56) had higher systolic blood pressure (160 +/- 26 mmHg vs 145 +/- 27 mmHg, P < 0.001) than the normoalbuminuric patients (n = 54). Both the AGT TT genotype (78.6% [44/56] vs. 55.6% [30/54], odds ratio [OR]: 3.0 [1.3-6.8]) and the T allele (88% [99/112] vs. 77% [83/108], OR: 2.5 [1.3-5.4]) were associated with an increased risk of albuminuria. Patients with the AGT TT genotype (n = 74) had higher 24-h UAE than those with the MT or MM genotypes (n = 36) (median: 37.8 mg/day vs. 17.8 mg/day, P < 0.01). This association remained significant in patients with normotension (56 mg/day [n = 19] for patients with the TT genotype vs. 22 mg/day [n = 14] for those with the MT/MM genotype, P = 0.03). The D allele carriers (DD or DI, n = 61) had higher serum ACE activities (75.5 +/- 29 U/l vs. 60.5 +/- 36.3 U/l, P < 0.01) than the noncarriers (II genotype). The median 24-h UAE also tended to be higher in the D allele carriers (38.9 mg/day vs. 21.4 mg/day, P = 0.07). The lowest UAE was observed in patients with the MM/MT/II genotype (16.3 mg/day [n = 18]) and the highest, in patients with the TT/DD/DI genotype (52.3 mg/day [n = 43]). No association was found between the TT genotype or D allele and hypertension.. The high frequencies of the TT genotype and T allele in Chinese populations may contribute to the high prevalence of albuminuria in patients with type 2 diabetes. The possibility of synergism between the AGT TT genotype and the ACE D allele should also be explored.

Topics: Adult; Age Factors; Aged; Albuminuria; Alleles; Amino Acid Substitution; Angiotensinogen; Biomarkers; Blood Pressure; Body Mass Index; Case-Control Studies; China; Cholesterol; Diabetes Mellitus, Type 2; DNA Transposable Elements; Female; Gene Frequency; Genes, ras; Genotype; Glycated Hemoglobin; Hong Kong; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Regression Analysis; Renin-Angiotensin System; Risk Factors; Sequence Deletion; Sex Factors; Time Factors

Recent studies have suggested an association between a deletion (D) variant of the angiotensin-converting-enzyme (ACE) gene and diabetic nephropathy. However, this finding has not been confirmed by all investigators. Furthermore, an M235T variant of the angiotensinogen (AGT) gene has been associated with hypertension, an important risk factor for the development and progression of diabetic nephropathy. The objective of our study was therefore to examine the relationship between these genetic variants of the renin-angiotensin system and diabetic nephropathy and hypertension, respectively, in a large (n = 661) group of Caucasian patients with insulin-dependent (n = 360) or non-insulin-dependent (n = 301) diabetes mellitus. The study had a power of 0.8 to detect a doubling of risk of nephropathy or hypertension in patients with the ACE-DD or AGT-235TT genotype, respectively. Allelic frequencies of the ACE-D and AGT-235T alleles were similar between patients with and without nephropathy in either type of diabetes, and accordingly, there was no significant association between diabetic nephropathy and the ACE or AGT genotype. Likewise, there was no significant association between the ACE or AGT genotype and hypertension. Thus, our data, in this large and ethnically homogeneous group of patients, do not support the hypothesis that these genetic variants of the renin-angiotensin system are strongly associated with either nephropathy or hypertension in patients with insulin-dependent or non-insulin-dependent diabetes mellitus. These genetic markers are therefore unlikely to serve as clinically useful predictors of either nephropathy or hypertension in Caucasian patients with diabetes.

Topics: Adult; Aged; Alleles; Angiotensinogen; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Gene Frequency; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Prospective Studies; Renin-Angiotensin System; Risk Factors; White People

To determine whether angiotensinogen (AGT) and angiotensin II type 1 (AT1) receptor genes contribute to the development of arterial hypertension in members of French Caucasian families and in subjects with hypertension associated with non-insulin-dependent diabetes mellitus (NIDDM).. Sibpair linkage analyses were performed with microsatellites near the AGT and AT1 receptor genes in 179 hypertensive sibpairs from 69 NIDDM kindreds. In addition, population/association studies were performed with the M235T and T174M polymorphisms of the AGT gene, and the A1166C polymorphism of the AT1 receptor gene.. No evidence for linkage between the AGT and AT1 receptor loci and hypertension was observed. In addition, the distributions of genotypes of AGT and AT1 receptor gene polymorphisms did not differ significantly among a group of unrelated individuals with both hypertension and NIDDM (n = 188) and three groups of unrelated control subjects with NIDDM (n = 117), hypertension (n = 75) or none of these conditions (n = 125).. These results suggest that the AGT and AT1 receptor genes are not major genetic determinants of hypertension associated with NIDDM in this population, although we can not exclude the possibility that these loci make a minor contribution in a polygenic context.

Topics: Aged; Angiotensinogen; Diabetes Mellitus, Type 2; Female; Genetic Linkage; Genotype; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System

Genotypic abnormalities of the renin-angiotensin system have been suggested as a risk factor for the development of microangiopathic complications in diabetic patients. We studied the relationship of either an insertion-deletion polymorphism in the angiotensin-converting enzyme (ACE) gene and the M235T and T174M variant polymorphisms of the angiotensinogen (AGT) gene in non-insulin-dependent diabetes mellitus (NIDDM) patients and its relationship with cardiovascular complications. A total of 193 NIDDM patients (89 men and 104 women aged 59.2 +/- 10.0 years; diabetes duration, 13.2 +/- 6.2 years) and 90 control subjects (42 men and 48 women aged 45.4 +/- 12.6 years) were recruited for the association study. Distribution of the genotype or allelic frequencies for all the studied polymorphisms did not differ significantly between controls and NIDDM patients. ACE and AGT genes did not display any difference in clinical or metabolic parameters according to each gene's genotype for either the control or the NIDDM group. For evaluation of nephropathy and retinopathy, NIDDM patients were matched with subjects not having microangiopathic complications. Thus, a total of 60 patients had diabetic nephropathy and were compared with 100 patients with normoalbuminuria. Sixty-eight NIDDM patients had diabetic retinopathy, and 92 patients presented no signs of retinopathy. There were no differences in genotypic or allelic distribution between NIDDM patients for either the presence or absence of retinopathy or nephropathy. We conclude that the ACE and AGT polymorphisms do not contribute to the genetic susceptibility to diabetic nephropathy and retinopathy in a caucasian Mediterranean population.

Topics: Aged; Alleles; Angiotensinogen; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; DNA Probes; Female; Genotype; Humans; Male; Mediterranean Sea; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Risk Factors; White People

To investigate predictive genetic markers for diabetic nephropathy, we studied the genetic polymorphisms of angiotensin-converting enzyme (ACE) and angiotensinogen (AGN) in Japanese subjects with non-insulin-dependent diabetes mellitus (NIDDM) with and without nephropathy. Genotype distributions were studied in 132 unrelated NIDDM patients of three groups with normoalbuminuria ([Normo] n = 53), microalbuminuria ([Micro] n = 54), and macroalbuminuria ([Macro] n = 25). The ACE insertion/deletion (I/D) polymorphism of intron 16 was identified by polymerase chain reaction, and the AGN M235T polymorphism was identified by restriction fragment length polymorphism analysis. There were no significant associations between AGN 235 allele or genotype and diabetic nephropathy. The D allele of ACE was significantly more frequent in the Micro (P = .003) and Macro (P = .009) group than in the Normo group. Overall frequencies of the ACE genotype did not differ significantly between the Micro and Macro groups. There were significant relationships between I/D polymorphism and plasma ACE activity; the DD genotype had the highest activity. A multiple logistic regression analysis revealed that the D allele is a strong and independent risk factor for abnormal albuminuria in NIDDM patients. These results suggested that ACE I/D polymorphism, but not AGN M235T polymorphism, is a possible genetic risk factor for diabetic nephropathy in Japanese NIDDM patients.

Topics: Aged; Albuminuria; Alleles; Angiotensinogen; Base Sequence; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Genotype; Humans; Logistic Models; Male; Middle Aged; Molecular Sequence Data; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Risk Factors

There is agreement that a family history of hypertension (HT), is a predictor for the risk of diabetic nephropathy (DN) in patients with type 2 diabetes, and possibly also type 1 diabetes. It follows that genes related to the risk of hypertension must also be considered candidate genes for DN. The 235T allele of the angiotensinogen gene was found to be related to primary HT.. To examine whether it is predictive for DN as well, we examined the angiotensinogen gene polymorphism in 230 healthy local controls, 423 patients with type 1 diabetes (n = 180 with DN; n = 243 without DN) and 663 patients with type 2 diabetes (n = 310 with DN; n = 353 without DN). The angiotensinogen gene M235T polymorphism was determined using PCR amplification.. The following results were obtained (i) no significant difference of genotype distribution (type 1: MM/MT/TT (%) 27.6/57.2/15.2 vs 27.2/56.1/16.7 (P = 0.92); type 2; MM/MT/TT (%) 31.7/48.2/2/20.1 vs. 32.9/46.8/20.3 (P = 0.93) or allele frequencies (type 1: M 0.56 vs. 0.55 (P = 0.795); type 2; M 0.56 vs. 0.56 (P = 0.86)) was found, between diabetic patients with or without DN, (ii) no difference was found between normotensive and hypertensive diabetic patients.. The data argue against a role of the angiotensinogen gene M235T polymorphism in the manifestation of diabetic nephropathy or hypertension in diabetic patients.

Topics: Adult; Age of Onset; Aged; Alleles; Angiotensinogen; Base Sequence; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; DNA Primers; Female; Gene Frequency; Humans; Hypertension; Male; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; Polymorphism, Genetic

Topics: Angiotensinogen; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Male; Polymorphism, Genetic