angiotensinogen and Diabetic-Retinopathy

Diabetic retinopathy is the most feared complication for those with diabetes. Although visible vascular pathology traditionally defines the management of this condition, it is now recognised that a range of cellular changes occur in the retina from an early stage of diabetes. One of the most significant functional changes that occurs in those with diabetes is a loss of vasoregulation in response to changes in neural activity. There are several retinal cell types that are critical for mediating so-called neurovascular coupling, including Müller cells, microglia and pericytes. Although there is a great deal of evidence that suggests that Müller cells are integral to regulating the vasculature, they only modulate part of the vascular tree, highlighting the complexity of vasoregulation within the retina. Recent studies suggest that retinal immune cells, microglia, play an important role in mediating vasoconstriction. Importantly, retinal microglia contact both the vasculature and neural synapses and induce vasoconstriction in response to neurally expressed chemokines such as fractalkine. This microglial-dependent regulation occurs via the vasomediator angiotensinogen. Diabetes alters the way microglia regulate the retinal vasculature, by increasing angiotensinogen expression, causing capillary vasoconstriction and contributing to a loss of vascular reactivity to physiological signals. This article summarises recent studies showing changes in vascular regulation during diabetes, the potential mechanisms by which this occurs and the significance of these early changes to the progression of diabetic retinopathy.

Topics: Angiotensinogen; Diabetes Mellitus; Diabetic Retinopathy; Humans; Microglia; Neurovascular Coupling; Retina; Retinal Vessels

Diabetic retinopathy (DR) is a major diabetes complication and the leading cause for vision loss and blindness in the adult human population. Diabetes, being an endocrinological disorder dysregulates a number of hormonal systems including the renin angiotensin system (RAS), which thereby may damage both vascular and neuronal cells in the retina. Angiotensin II (Ang II), an active component of the RAS is increased in diabetic retina, and may play a significant role in neurovascular damage leading to the progression of DR. In this review article, we highlight the role of Ang II in the pathogenesis of retinal damage in diabetes and discuss a newly identified mechanism involving tissue chymase and angiotensin-(1-12) [Ang-(1-12)] pathways. We also discuss the therapeutic effects of potential RAS inhibitors targeting blockade of cellular Ang II formation to prevent/ protect the retinal damage. Thus, a better understanding of Ang II formation pathways in the diabetic retina will elucidate early molecular mechanism of vision loss. These concepts may provide a novel strategy for preventing and/or treating diabetic retinopathy, a leading cause of blindness worldwide.

Topics: Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Chymases; Diabetic Retinopathy; Humans; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System

Topics: Aldehyde Reductase; Angiotensinogen; Apolipoproteins E; Arteriosclerosis; Aryldialkylphosphatase; Diabetic Nephropathies; Diabetic Retinopathy; Disease Progression; DNA, Mitochondrial; Esterases; Humans; Methylenetetrahydrofolate Reductase (NADPH2); Oxidoreductases Acting on CH-NH Group Donors; Peptidyl-Dipeptidase A; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic; Receptor for Advanced Glycation End Products; Receptors, CCR5; Receptors, Immunologic; Risk Factors

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

This study intends to explore the role of microRNA-29a (miRNA-29a) in the development of diabetic retinopathy by targeting AGT gene in a rat model.. Fifty-six DR rat models were established and divided into 7 groups (with 8 rats in each group): the model group, the miRNA-29a group, the miRNA-29a knockdown group, the negative control (NC) group, the AGT group, the miRNA-29a+AGT group, and the miRNA-29a knockdown+AGT group respectively, while 8 normal rats were selected as the normal group. The qRT-PCR was used to detect the expression of miRNA-29a and AGT mRNA. The AGT protein expression was measured using Western blotting. The ADPase histochemical staining was applied to detect retinal neo-vascular morphology. The number of retinal vascular endothelial cells was counted by H&E staining.. MiRNA-29a and AGT mRNA expressions were negatively correlated. Compared with rats in the normal group, the miRNA-29a expression in DR rats of each group decreased, but the AGT mRNA and protein expression increased; the vascular distribution was in disorder, and the new retinal vessels, vascular density, and endothelial nuclei all increased. Compared with the model group, miRNA-29a increased, and the AGT mRNA and protein expression decreased in the miRNA-29a group; additionally, the vascular density, tortuosity, and endothelial cell nuclei significantly decreased. The opposite trend was found in the miRNA-29a knockdown group, the miRNA-29a knockdown+AGT group, and the AGT group, particularly in the miRNA-29a knockdown+AGT group.. Overexpression of miRNA-29a could down-regulate AGT expression, thereby preventing the development of DR in a rat model.

Topics: Angiotensinogen; Animals; Blood Glucose; Diabetic Retinopathy; Disease Models, Animal; Endothelial Cells; Gene Knockdown Techniques; HEK293 Cells; Humans; Male; MicroRNAs; Rats; Rats, Sprague-Dawley; Retina; RNA, Messenger; Transfection

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

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

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

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

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

Recent studies have suggested that an inherited predisposition to essential hypertension may increase susceptibility to nephropathy for patients with IDDM. Essential hypertension has been linked to the angiotensinogen (AGT) gene in genetic linkage studies in American and European populations. A molecular variant (M235T), which has a functional effect, has been described with highest plasma AGT levels being associated with the TT genotype. In a case-control study, we have evaluated the role of this functional genetic marker in patients with IDDM and nephropathy and in IDDM patients without nephropathy. We studied 195 IDDM patients, of whom 95 had established diabetic nephropathy; the remaining 100 patients, who had no evidence of microalbuminuria, served as control subjects. All patients were whites born in Northern Ireland. The point mutation in the AGT gene was analyzed using restriction typing. The background frequency of the M235T variant was assessed in 80 healthy blood donors, and the TT genotype was present in 9%. This genotype occurred in 8% of control IDDM patients without nephropathy and 19% of IDDM patients with nephropathy (P = 0.025). The odds ratio for diabetic nephropathy associated with the TT genotype was 2.7 (95% CI 1.04-7.52). There was no relationship between blood pressure and AGT genotypes in the control group. We cannot exclude the possibility that the observed association in the nephropathy group is due to an association between AGT genotype and hypertension. This evidence may help to explain the predisposition to diabetic nephropathy afforded by hypertension and merits further investigation.

Topics: Adult; Age of Onset; Albuminuria; Angiotensinogen; Base Sequence; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; DNA Primers; Female; Genetic Variation; Genotype; Glycated Hemoglobin; Humans; Hypertension; Male; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; Polymorphism, Genetic; Reference Values; Restriction Mapping