angiotensinogen and Diabetic-Angiopathies

Topics: Aldehyde Reductase; Angiotensinogen; Apolipoproteins E; Diabetic Angiopathies; Genetic Linkage; Genetic Predisposition to Disease; Humans; Peptidyl-Dipeptidase A; Plasminogen Activator Inhibitor 1; Vascular Endothelial Growth Factor A

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

Topics: Angiotensinogen; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Humans; Peptidyl-Dipeptidase A; Risk Factors

Variations of glucose level represent the major cause of diabetic micro- and macroangiopathy, but other factors play a significant role on the occurrence of the complications, which is difficult to quantify. We will review the genetic factors which modulate vascular and heart response to diabetes. In an attempt to modelize a complex disease, we will distinguish susceptibility gene for the deleterious effects of hyperglycemia, through advanced glycation end-products (AGE), and genes responsible for associated and interacting, diseases, such as hypertension and atherosclerosis. We examine, in particular, the possible interactions of the products of these genes on target organs.

Topics: Angiotensinogen; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Humans; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptors, Angiotensin

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

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

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

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

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

Patients with insulin-dependent diabetes mellitus (IDDM) have a high risk of developing diabetic nephropathy, retinopathy and cardiovascular diseases. The contribution of gene polymorphisms of the renin angiotensin system to these complications is controversial and may differ among populations.. In 257 Dutch IDDM patients (188 with urinary albumin excretion (UAE) <30 mg/24 h), logistic regression analysis was used to study the relationships among, on the one hand, the insertion/deletion gene polymorphism of the angiotensin-converting enzyme gene (ACE-ID), the M235T gene polymorphism of the angiotensinogen gene (AGT-M235T), and the A1166C gene polymorphism of the angiotensin type 1 receptor gene (AT1-A1166C), and, on the other hand, UAE, retinopathy, hypertension, and coronary heart disease.. The T-allele of the AGT-M235T polymorphism was associated with an increased risk of an elevated UAE (odds ratio (OR) 3.03; 95% confidence interval (CI) 1.06-8.61), but only when interaction with the D-allele of the ACE-ID polymorphism was considered. A previously described positive interaction between the T-allele of the AGT-M235T polymorphism and the D-allele of the ACE-ID polymorphism could not be confirmed. The T-allele was also associated with an increased risk of retinopathy (OR 3.89, 95% CI 1.79-8.47). The CC-genotype of the AT1-A1166C polymorphism was associated with hypertension (OR 3.58; 95% CI 1. 23-10.37).. In a Dutch IDDM population, including 69 patients with (incipient) diabetic nephropathy, the T-allele of the AGT-M235T polymorphism is associated with an elevated UAE and diabetic retinopathy and the CC-genotype of the AT1-A1166C polymorphism is associated with hypertension. A previously described interaction between the AGT-M235T and the ACE-ID polymorphisms could not be confirmed. Since the number of nephropathic patients in this study is small, these conclusions must be interpreted with caution.

Topics: Adult; Aged; Albuminuria; Angiotensinogen; Coronary Disease; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; DNA Transposable Elements; Gene Deletion; Humans; Hypertension; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System

In a hospital cohort study, we examined whether or not ACE (Angiotensin-I converting enzyme) and AGT (Angiotensinogen) gene polymorphisms were associated with the development of nephropathy in long-term Japanese insulin-dependent diabetes mellitus (IDDM) patients with or without proliferative retinopathy, and whether or not the polymorphisms were associated with an arteriosclerotic family history in first degree relatives of the patients. A total of 201 patients with IDDM for more than 10 years and 159 patients with IDDM for more than 15 years were randomly selected in our hospital. All patients received uniform diabetes management and were divided into three groups, no nephropathy, incipient nephropathy and clinical nephropathy groups. There were no differences in clinical characteristics excluding urinary albumin to creatinine ratio and systolic blood pressure between the three groups. ACE I/D polymorphism was related to plasma ACE activity, but there were no associations between ACE I/D polymorphism and the development of diabetic nephropathy, nor was renal deterioration observed in patients with proliferative retinopathy even in those with a history of diabetes for more than 15 years. The AGT polymorphism did not have an additive effect on the association between ACE polymorphism and the development of diabetic nephropathy in patients with or without retinopathy. Development of diabetic nephropathy in the patients with or without proliferative retinopathy did not result in ACE or AGT polymorphisms. On the other hand, the ACE DD genotype was associated with a family history of ischemic heart disease in first degree relatives (X2 score = 9.04, P < 0.05). ACE and AGT gene polymorphisms may not play a role in the protective or accelerative effect against the development of diabetic nephropathy in the patients with or without proliferative retinopathy, but ACE gene polymorphism might be related to an arteriosclerotic family history in Japanese IDDM patients.

Topics: Adult; Albuminuria; Angiotensinogen; Blood Pressure; Cohort Studies; Creatine; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; DNA; Female; Glycated Hemoglobin; Humans; Hypertension; Japan; Male; Myocardial Ischemia; Ophthalmoscopy; Peptidyl-Dipeptidase A; Point Mutation; Polymorphism, Genetic; Renin-Angiotensin System

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

The allele 235T (a threonine in place of a methionine at position 235) of angiotensinogen has been found to be associated with a predisposition to essential hypertension. We investigated whether this allele also confers increased susceptibility to nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). A group of 380 patients who had had IDDM for 15 to 20 years were genotyped at the angiotensinogen 235 locus. Included were 75 patients with normoalbuminuria (albumin excretion rate < 30 micrograms/min), two series of patients with microalbuminuria (n = 30 and n = 136), and two series with overt proteinuria (n = 41 and n = 98). Allele 235T frequency was higher among cases with microalbuminuria (0.41 in the two series combined) or overt proteinuria (0.40) than in the normoalbuminuria group (0.36). However, this difference was not statistically significant with this sample size (chi 2 = 1.2, P = NS with 2 df). Under a recessive model, allele 235T homozygotes had a 1.6-fold risk of developing nephropathy relative to carriers of other genotypes, but this value was not significantly different from 1(95% CI = 0.8 to 3.5). The strength of the association did not improve after stratification by degree of glycemic control. With respect to the hypertension in these IDDM patients, no association with allele 235T was found. Allele 235T frequencies in normotensive and hypertensive individuals were 0.363 and 0.353, respectively, among normoalbuminuric IDDM individuals (chi 2 = 0.01, P = NS) and 0.411 and 0.414 among microalbuminuric IDDM subjects (chi 2 = 0.0, P = NS). We conclude that the angiotensinogen polymorphism M235T might influence susceptibility to nephropathy in insulin-dependent diabetes, but its effect, if any, is rather small and independent of hypertension.

Topics: Adult; Alleles; Angiotensinogen; Base Sequence; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Genetic Predisposition to Disease; Humans; Hypertension; Molecular Probes; Molecular Sequence Data; Polymorphism, Genetic

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