angiotensin-i and Diabetic-Angiopathies

Type 2 diabetes mellitus (T2DM) is an increasing problem in childhood; however type 1 diabetes mellitus (T1DM) remains by far the most common type of diabetes in this age group. In this review we will focus on T1DM, because this will have the greatest implication for patients diagnosed in childhood. During the atherosclerotic process, several molecular, receptorial and cellular factors provide a continous mechanism of vascular damage. In diabetic children this state seems to be enhanced and facilitated so that accelerated atherosclerosis is associated with an increased risk of cardiovascular events in respect to the non diabetic population. Hyperglycemia PER SE and associated with diabetes is an important risk factor for atherosclerosis. At present a substantial part of children with diabetes do not reach satisfactory glycemic control. Other risk factors for the development and progression of atherosclerosis may be inherited or develop in the course of the disease: hypertension, dyslipidemia, insulin resistance, obesity, cigarette smoking, physical inactivity, disturbance of platelet function, coagulation and fibrinolysis. The development and progression of atherosclerosis should be blocked at an early age, if possible. Primary prevention to all risk factors for cardiovascular disease is important and intervention is indicated if necessary. At the moment the best therapeutic strategy is to maintain metabolic control at a physiologic level and perform screening and early intervention for vascular complications.

Topics: Adult; Angiotensin I; Angiotensin II; Atherosclerosis; Child; Cholesterol, LDL; Diabetic Angiopathies; Fatty Liver; Humans; Inflammation; Macrophages; Thrombosis

In chronic heart failure there is gradual reactivation of vascular tissue angiotensin I (AI) to angiotensin II (AII) conversion over time in patients taking chronic ACE inhibitor therapy. However, it remains unknown whether the same overall phenomenon occurs in other patients taking chronic ACE inhibitor therapy, such as patients with type 2 diabetes mellitus.. We studied 30 patients with type 2 diabetes mellitus (mean age 43.5 +/- 10.8 years), all of whom received lisinopril (20 mg/day) as part of their normal treatment. Over the course of the 18 month study, we made measurements at 0, 9 and 18 months. These measurements included plasma values for components of the renin-angiotensin-aldosterone system. In addition, we infused AI and AII into the brachial arteries of patients to assess vascular tissue AI to AII conversion.. There were no significant changes in plasma renin activity, ACE, AI, AII or aldosterone during the study. In contrast, vascular AI to AII conversion was significantly (p = 0.01) greater at 18 months than at 0 months. There was no change over time in the response to infused AII.. We have shown in vivo that vascular tissue AI to AII conversion gradually increases over time in patients with type 2 diabetes being treated with lisinopril. Further studies are required to determine whether this reactivation detracts from the cardioprotective effects of chronic ACE inhibitor therapy in diabetic patients, and if so, how best to overcome it.

Topics: Adult; Aged; Aldosterone; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Flow Velocity; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Hypertension; Kinetics; Lisinopril; Male; Middle Aged

This study aimed to investigate OIP5-AS1 effects on microangiopathy in diabetic mouse.. The expression levels of OIP5-AS1, miR-200b, and ACE2 expression were measured by RT-qPCR. Western blot was conducted to detect The ACE2 and Ang-(1-7) expression. Luciferase reporter assays were used to identify the interaction between miR-200b and OIP5-AS1 or ACE2. Morris water maze test was performed for detecting cognitive function.. Our results indicated that diabetic mice exhibited much lower OIP5-AS1 expression in the hippocampus than normal mice. Diabetic mice of OIP5-AS1 KO group showed remarkably lower OIP5-AS1 expression in the hippocampus, longer escape latency and lower percentage of CD31+ cells in the hippocampusthan those of WT group. OIP5-AS1 knockdown directly up-regulated miR-200b expression and ACE2 was directly inhibited by miR-200b. Relative to normal mice, diabetic mice had markedly higher miR-200b expression and lower ACE2 expression in the hippocampus. Diabetic mice of OIP5-AS1 KO group were with obviously higher miR-200b expression and lower ACE2 expression in the hippocampus than those of WT group. Compared with diabetic mice of OIP5-AS1 KO group, those of WT group, OIP5-AS1 KO + miR-200b inhibitor group and OIP5-AS1 KO + ACE2 group had obviously shorter escape latency and higher percentage of CD31. OIP5-AS1 attenuated microangiopathy in diabetic mouse by regulating miR-200b/ACE2.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Caspase 3; Cognition; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Gene Knockdown Techniques; Hippocampus; Maze Learning; Mice; Mice, Knockout; MicroRNAs; Peptide Fragments; Peptidyl-Dipeptidase A; Platelet Endothelial Cell Adhesion Molecule-1; RNA, Long Noncoding

Diabetes is one of the most common diseases in today's society. Diabetes can cause multiple vascular lesions in the body, renal insufficiency, blindness, and so on. However, the evidence concerning the role of extracorporeal shock wave therapy in diabetic vascular disease is insufficient.. Observation of the effect of shock wave on vascular lesions in diabetic rats.. This study used an experimental design.. The research took place in the laboratory research center at The Third Military Medical University.. Eighteen healthy adult male Sprague Dawley rats were randomly divided into 3 groups: normal control group (group A), diabetic group (group B), and diabetes + shock wave treatment group (group C). Groups B and C were established by intraperitoneal injection of streptozotocin 60 mg/kg to demonstrate a diabetic rat model. Shock wave treatment was performed on the left lower extremity femoral artery in group C for 1 week (T1), 2 weeks (T2), 3 weeks (T3), and 4 weeks (T4) while the other 2 groups were reared normally. At the end of T4 shock wave treatment, the femoral arteries of each group were observed under an electron microscope. The expression of vascular endothelial growth factors (VEGF), endothelial nitric oxide synthase (eNOS), and angiotensin type 1 (AT1) were measured by western blot, and the changes of VEGF expression were detected by real-time polymerase chain reaction.. The VEGF and eNOS in group C were higher than those in group B (P < 0.05). The AT1 of the rats in the B and C groups was significantly higher than that in the A group (P < 0.05), but the C group was significantly lower than the B group (P < 0.05). After shock wave therapy, the surface of vascular endothelium in group C was flatter and smoother than that in group B, and the endothelial basement membrane and foot process were relatively tight.. Potential mechanisms that underlie the relationship between vascular dysfunction and diabetic neuropathy pain were not examined in this study.. Shock wave may promote the formation of new blood vessels and improve vasomotor function by upregulating VEGF, eNOS, and downregulation of AT1 in diabetic rats and improve the damage of blood glucose to blood vessels to some extent.. Shock wave, diabetic rats, vascular dysfunction, neovascularization.

Topics: Angiotensin I; Animals; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Endothelium, Vascular; High-Energy Shock Waves; Male; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor A

Diabetes mellitus, a metabolic disorder with significant global health care burden, causes chronic microvascular and macrovascular complications that still comprise a therapeutic challenge. Angiotensin-(1-7), a heptapeptide with vasodilatory properties, has been found to restore vascular reactivity and endothelial cell function, mostly in experiments on larger isolated animal vessels and in cell cultures. The presented hypothesis suggests that angiotensin-(1-7) might have beneficial effects on microvascular function that is damaged in diabetic patients, alleviating endothelial dysfunction and increasing microvascular reactivity to various vasoactive agents in diabetes. It is further proposed that iontophoresis with angiotensin-(1-7) might be used to explore this potential beneficial effect, as well as provide a possible future therapeutic delivery method for angiotensin-(1-7). Since other peptides and proteins have been previously tested and used in iontophoretic transdermal delivery, it is plausible that angiotensin-(1-7) would be a suitable candidate for transdermal iontophoretic application for research (and potentially therapeutic) purposes. If confirmed, the delineated hypothesis would have immense implications for more effective care of diabetic patients, as well as for better understanding of microcirculatory pathophysiological mechanisms in diabetes.

Topics: Angiotensin I; Animals; Diabetes Complications; Diabetic Angiopathies; Disease Models, Animal; Endothelial Cells; Humans; Iontophoresis; Mice; Microcirculation; Models, Theoretical; Peptide Fragments; Rats; Skin

Previously, a facilitating effect of hyperbaric oxygenation (HBO₂) on aortic ring responses to angiotensin-(1-7) in healthy rats was reported, with epoxyeicosatrienoic acids (EETs) possibly playing an important role. The aim of this study was to assess whether HBO₂ exerts similar effects in diabetic rats and to further explore the role of specific cytochrome P450 (CYP) enzymes in changes induced by HBO₂. Aortic relaxation to angiotensin-(1-7) was significantly higher in HBO₂ diabetic rats compared to control diabetic rats, while HBO₂ had no effect on angiotensin II contraction. N-methylsulphonyl-6-(2-propargyloxyphenyl/hexanamide inhibited the facilitation of angiotensin-(1-7) responses in HBO₂ rats, suggesting an important role of EETs in this modulation. mRNA expression of CYP2J3 and protein expression of CYP2C11 were significantly upregulated in HBO₂ diabetic rats, whereas CYP4A1, CYP4A2 and CYP4A3 mRNA and CYP2J3 protein expression was similar between groups. Mean arterial pressure, ferric reducing ability of plasma and Thiobarbituric Acid Reactive Substances levels and serum angiotensin-(1-7) concentrations were not significantly changed.

Topics: 8,11,14-Eicosatrienoic Acid; Amides; Angiotensin I; Angiotensin II; Animals; Aorta, Thoracic; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Enzyme Induction; Enzyme Inhibitors; Hyperbaric Oxygenation; Male; Oxidative Stress; Peptide Fragments; Rats, Sprague-Dawley; Steroid 16-alpha-Hydroxylase; Vascular Resistance; Vasoconstriction; Vasodilation; Vasodilator Agents

We investigated the changes and the molecular mechanisms of cerebral vascular damage and tested the therapeutic effects of Niaspan in type-1 streptozotocin induced diabetic (T1DM) rats after stroke. T1DM-rats were subjected to transient middle cerebral artery occlusion (MCAo) and treated without or with Niaspan. Non-streptozotocin rats (WT) were also subjected to MCAo. Functional outcome, blood-brain-barrier (BBB) leakage, brain hemorrhage, immunostaining, and rat brain microvascular endothelial cell (RBEC) culture were performed. Compared to WT-MCAo-rats, T1DM-MCAo-rats did not show an increase lesion volume, but exhibited significantly increased brain hemorrhage, BBB leakage and vascular damage as well as decreased functional outcome after stroke. Niaspan treatment of stroke in T1DM-MCAo-rats significantly attenuated BBB damage, promoted vascular remodeling and improved functional outcome after stroke. T1DM-MCAo-rats exhibited significantly increased Angiopoietin 2 (Ang2) expression, but decreased Ang1 expression in the ischemic brain compared to WT-MCAo-rats. Niaspan treatment attenuated Ang2, but increased Ang1 expression in the ischemic brain in T1DM-MCAo-rats. In vitro data show that the capillary-like tube formation in the WT-RBECs marginally increased compared to T1DM-RBEC. Niaspan and Ang1 treatment significantly increased tube formation compared to non-treatment control. Inhibition of Ang1 attenuated Niacin-induced tube formation in T1DM-RBECs. Niaspan treatment of stroke in T1DM-rats promotes vascular remodeling and improves functional outcome. The Ang1/Ang2 pathway may contribute to Niaspan induced brain plasticity. Niaspan warrants further investigation as a therapeutic agent for the treatment of stroke in diabetics.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Glucose; Blood-Brain Barrier; Cerebral Hemorrhage; Cerebrovascular Circulation; Cholesterol, HDL; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Disease Models, Animal; Infarction, Middle Cerebral Artery; Male; Niacin; Rats; Rats, Wistar; Vasodilator Agents

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 aim of this study was to test the hypothesis that treatment with angiotensin-(1-7) [ANG-(1-7)] or ANG-(1-7) nonpeptide analog AVE-0991 can produce protection against diabetes-induced cardiovascular dysfunction. We examined the influence of chronic treatment (4 wk) with ANG-(1-7) (576 microg.kg(-1).day(-1) ip) or AVE-0991 (576 microg.kg(-1).day(-1) ip) on proteinuria, vascular responsiveness of isolated carotid and renal artery ring segments and mesenteric bed to vasoactive agonists, and cardiac recovery from ischemia-reperfusion in streptozotocin-treated rats (diabetes). Animals were killed 4 wk after induction of diabetes and/or treatment with ANG-(1-7) or AVE-0991. There was a significant increase in urine protein (231 +/- 2 mg/24 h) in diabetic animals compared with controls (88 +/- 6 mg/24 h). Treatment of diabetic animals with ANG-(1-7) or AVE-0991 resulted in a significant reduction in urine protein compared with vehicle-treated diabetic animals (183 +/- 16 and 149 +/- 15 mg/24 h, respectively). Treatment with ANG-(1-7) or AVE-0991 also prevented the diabetes-induced abnormal vascular responsiveness to norepinephrine, endothelin-1, angiotensin II, carbachol, and histamine in the perfused mesenteric bed and isolated carotid and renal arteries. In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly better in ANG-(1-7)- or AVE-0991-treated animals. These results suggest that activation of ANG-(1-7)-mediated signal transduction could be an important therapeutic strategy to reduce cardiovascular events in diabetic patients.

Topics: Angiotensin I; Animals; Blood Pressure; Cardiotonic Agents; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Dose-Response Relationship, Drug; Male; Peptide Fragments; Rats; Rats, Wistar; Streptozocin; Vasoconstriction; Vasodilation; Ventricular Dysfunction, Left

Amylin (or islet amyloid polypeptide) has been reported to have binding sites in the central nervous system and the kidney and has been shown to activate plasma renin. It has been postulated that this peptide may be an important mechanistic link between hypertension and diabetes in the insulin resistance syndrome. To explore this issue, the effects of rat amylin on mean arterial blood pressure were investigated in anaesthetised rats. Amylin elicited a pressor response of approximately 10 mmHg (maximal at 100 pmol.kg-1) which was apparent within 30-60 s and persisted over 15 min. At higher concentrations amylin elicited a hypotensive response (negative log IC50 8.52 mol.kg-1). The novel amylin receptor antagonist AC413 (12 nmol.kg-1.min-1) reduced the pressor response but not the hypotensive effects of amylin. The peptide antagonist calcitonin gene-related peptide (CGRP)8-37 (12 nmol.kg-1.min-1) reduced the pressor response elicited by amylin and also antagonized the hypotensive effect of amylin. Pre-treatment of animals with the ganglion blocker mecamylamine (3 mg.kg-1 s.c.) reduced the pressor effect of amylin. Following the administration of the angiotensin converting enzyme inhibitor ramiprilat (300 nmol.kg-1 i.v.) the pressor response to amylin was reduced. Salmon calcitonin also elevated blood pressure in the anaesthetised rat; doses of amylin and salmon calcitonin associated with a pressor effect were associated with increases in plasma renin activity. We conclude that amylin may act centrally to elevate blood pressure in the anaesthetised rat, possibly through activation of the renin angiotensin system.

Topics: Amino Acid Sequence; Amyloid; Anesthesia, General; Angiotensin I; Animals; Blood Pressure; Calcitonin; Calcitonin Gene-Related Peptide; Diabetic Angiopathies; Ganglionic Blockers; Humans; Hypertension; Hypotension; Islet Amyloid Polypeptide; Male; Mecamylamine; Molecular Sequence Data; Peptide Fragments; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Islet Amyloid Polypeptide; Receptors, Peptide; Recombinant Fusion Proteins; Salmon