Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that angiopoietins (Angs) and their receptor, Tie2, play a role in vascular integrity and neovascularization. The renin-angiotensin system has been hypothesized to contribute to the development of diabetic retinopathy. In this study, we investigated the effect of angiotensin II (AII) on Ang1 and Ang2 expression in cultured bovine retinal endothelial cells (BRECs). AII stimulated Ang2 but not Ang1 mRNA expression in a dose- and time-dependent manner. This response was inhibited completely by angiotensin type 1 receptor (AT1) antagonist. AII increased the transcription of Ang2 mRNA, but did not change the half-life. Protein kinase C (PKC) inhibitor completely inhibited AII-induced Ang2 expression, and the mitogen-activated protein kinase (MAPK) inhibitor also inhibited it by 69.4+/-15.6%. In addition, we confirmed the upregulation of Ang2 in an AII-induced in vivo rat corneal neovascularization model. These data suggest that AII stimulates Ang2 expression through AT1 receptor-mediated PKC and MAPK pathways in BREC, and AII may play a novel role in retinal neovascularization.
Diabetes 2001 Apr
PMID:Angiotensin II induces expression of the Tie2 receptor ligand, angiopoietin-2, in bovine retinal endothelial cells. 1128 54

Diabetic retinopathy remains a leading cause of irreversible blindness. A critical early pathology in the disease is the adhesion of leukocytes to the retinal vasculature, a process that occurs, in part, via intercellular adhesion molecule-1. Once leukocyte adhesion occurs, endothelial cell injury ensues, as does blood-retinal barrier breakdown. Here we show that angiopoietin-1 can prevent and reverse these diabetic retinal vascular changes in both new and established diabetes. Angiopoietin-1, when given intravitreally to newly diabetic rats, normalized retinal vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 mRNA and protein levels, leading to reductions in leukocyte adhesion, endothelial cell injury, and blood-retinal barrier breakdown. When an adenovirus coding for angiopoietin-1 was given systemically to mice with established diabetes, it similarly inhibited leukocyte adhesion and endothelial cell injury and blood-retinal barrier breakdown. These changes coincided with reductions in retinal eNOS, nitric oxide, Akt (protein kinase B), and MAP kinase activity, known mediators of VEGF bioactivity and leukocyte adhesion. When endogenous VEGF bioactivity was inhibited with a soluble Flt-1/Fc chimera, retinal Akt kinase activity was significantly reduced in vivo. Taken together, these data document new vascular and anti-inflammatory bioactivities for angiopoietin-1 and identify it as the first naturally occurring protein that directly protects the retinal vasculature in diabetes.
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PMID:Suppression of diabetic retinopathy with angiopoietin-1. 1200 Jul 4

Angiopoietins are a recently discovered family of growth factors which act on endothelial cells via Tie receptors. They are widely expressed and have essential roles in regulating vascular growth, development, maturation and permeability. Disturbances in microvascular regulation play an important part in a number of diseases prominent in the developed world including diabetes, ischemic heart disease and cancer. It is the interplay between angiopoietins and other factors including vascular endothelial growth factor (VEGF) which determines endothelial behavior both in health and in these diseases. Angiopoietin-1 is unique in its ability to reduce endothelial permeability and it antagonises the effects of VEGF in its permeability and angiogenesis-inducing actions. The renal glomerulus constitutes a highly specialized microcirculation in which the permeability characteristics of the capillary wall allow its unique filtration function. Disturbance of this function may cause a reduction in glomerular filtration rate or proteinuria. Understanding of the regulation of the filtration barrier is incomplete but the expression of angiopoietins in the glomerulus suggests a mechanism for maintenance of the glomerular endothelium and modulation of the actions of glomerular VEGF. As has been clearly shown for VEGF, angiopoietins are likely to be involved in glomerular disease and recovery from it. Manipulation of angiopoietins has a wide range of potential therapeutic applications from inhibition of diabetic retinal neovascularisation to promotion of glomerular repair.
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PMID:Angiopoietins: microvascular modulators with potential roles in glomerular pathophysiology. 1276 63

Pericyte loss is an early pathologic feature of diabetic retinopathy, consistently present in retinae of diabetic humans and animals. Because pericyte recruitment and endothelial cell survival are controlled, in part, by the angiopoietin/Tie2 ligand/receptor system, we studied the expression of angiopoietin-2 and -1 in relation to the evolution of pericyte loss in diabetic rat retinae, using quantitative retinal morphometry, and in retinae from mice with heterozygous angiopoietin deficiency (Ang-2 LacZ knock-in mice). Finally, recombinant angiopoietin-2 was injected into eyes of nondiabetic rats, and pericyte numbers were quantitated in retinal capillaries. Angiopoietin-1 protein was present in the normal maturing retina and was upregulated 2.5-fold in diabetic retinae over 3 months of diabetes. In contrast, angiopoietin-2 protein was consistently upregulated more than 30-fold in the retinae of diabetic rats, preceding the onset of pericyte loss. Heterozygous angiopoietin-2 deficiency completely prevented diabetes-induced pericyte loss and reduced the number of acellular capillary segments. Injection of angiopoietin-2 into the eyes of normal rats induced a dose-dependent pericyte loss. These data show that upregulation of angiopoietin-2 plays a critical role in the loss of pericytes in the diabetic retina.
Diabetes 2004 Apr
PMID:Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy. 1504 28

In the early stage of diabetic nephropathy (one of the major microvascular complications of diabetes) glomerular hyperfiltration and hypertrophy are observed. It is clinically important to regulate glomerular hypertrophy for preventing glomerulosclerosis. The number of glomerular endothelial cells is known to be increased in diabetic nephropathy associated with enlarged glomerular tufts, suggesting that the mechanism is similar to that of angiogenesis. Tumstatin peptide is an angiogenesis inhibitor derived from type IV collagen and inhibits in vivo neovascularization induced by vascular endothelial growth factor (VEGF), one of the mediators of glomerular hypertrophy in diabetic nephropathy. Here, we show the effect of tumstatin peptide in inhibiting alterations in early diabetic nephropathy. Glomerular hypertrophy, hyperfiltration, and albuminuria were suppressed by tumstatin peptide (1 mg/kg) in streptozotocin-induced diabetic mice. Glomerular matrix expansion, the increase of total glomerular cell number and glomerular endothelial cells (CD31 positive), and monocyte/macrophage accumulation was inhibited by tumstatin peptide. Increase in renal expression of VEGF, flk-1, and angiopoietin-2, an antagonist of angiopoietin-1, was inhibited by tumstatin treatment in diabetic mice. Alteration of glomerular nephrin expression, a podocyte protein crucial for maintaining glomerular filtration barrier, was recovered by tumstatin in diabetic mice. Taken together, these results demonstrate the potential use of antiangiogenic tumstatin peptide as a novel therapeutic agent in early diabetic nephropathy.
Diabetes 2004 Jul
PMID:Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy. 1522 Feb 8

Diabetic nephropathy is one of the major microvascular complications in diabetes and is the leading cause of end-stage renal disease worldwide. Among various factors, angiogenesis-associated factors such as vascular endothelial growth factor (VEGF)-A and angiopoietin (Ang)-2 are involved in the development of diabetic nephropathy. We previously reported the therapeutic efficacy of antiangiogenic tumstatin peptide in the early diabetic nephropathy model. Here, we examine the effect of endostatin peptide, a potent inhibitor of angiogenesis derived from type XVIII collagen, in preventing progression in the type 1 diabetic nephropathy mouse model. Endostatin peptide did not affect hyperglycemia induced by streptozotocin (STZ). Glomerular hypertrophy, hyperfiltration, and albuminuria were significantly suppressed by endostatin peptide (5 mg/kg) in STZ-induced diabetic mice. Glomerular mesangial matrix expansion, the increase of glomerular type IV collagen, endothelial area (CD31(+)), and F4/80(+) monocyte/macrophage accumulation were significantly inhibited by endostatin peptide. Increase in the renal expression of VEGF-A, flk-1, Ang-2, an antagonist of angiopoietin-1, transforming growth factor-beta1, interleukin-6, and monocyte chemoattractant protein-1 was inhibited by endostatin peptide in diabetic mice. Decrease of nephrin mRNA and protein in diabetic mice was suppressed by treatment with endostatin peptide. The level of endostatin in the renal cortex and sera was increased in diabetic mice. Endogenous renal levels of endostatin were decreased in endostatin peptide-treated groups in parallel with VEGF-A. Although serum levels of endostatin were decreased in the low-dose endostatin-peptide group, high-dose administration resulted in elevated serum levels of endostatin. These results demonstrate the potential use of antiangiogenic endostatin peptide as a novel therapeutic agent in diabetic nephropathy.
Diabetes 2005 Oct
PMID:Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model. 1618 90

Microvascular dysfunction is a major cause of impaired wound healing seen in diabetic patients. Therefore, reestablishment of structural and functional microvasculature could be beneficial to promote wound healing in these patients. Angiopoietin-1 (Ang1) is a specific growth factor functioning to generate a stable and functional vasculature through the Tie2 and Tie1 receptors. Here we determined the effectiveness of cartilage oligomeric matrix protein (COMP)-Ang1, a soluble, stable, and potent form of Ang1, on promotion of healing in cutaneous wounds of diabetic mice. An excisional full-thickness wound was made in the dorsal side of the tail of diabetic (db/db) mice, and mice were then treated systemically with adenovirus (Ade) encoding COMP-Ang1 or with control virus encoding beta-gal (Ade-beta-gal) or treated topically with recombinant COMP-Ang1 protein or BSA. Time course observations revealed that mice treated with Ade-COMP-Ang1 or COMP-Ang1 protein showed accelerated wound closure and epidermal and dermal regeneration, enhanced angiogenesis and lymphangiogenesis, and higher blood flow in the wound region compared with mice treated with control virus or BSA. COMP-Ang1 promotion of wound closure and angiogenesis was not dependent on endothelial nitric oxide synthase or inducible nitric oxide synthase alone. Taken together, these findings indicate that COMP-Ang1 can promote wound healing in diabetes through enhanced angiogenesis, lymphangiogenesis, and blood flow.
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PMID:COMP-angiopoietin-1 promotes wound healing through enhanced angiogenesis, lymphangiogenesis, and blood flow in a diabetic mouse model. 1654 81

Parathyroid hormone (PTH) is a major regulatory factor in skeletal physiology. However, the molecular mechanism underlying the effects of PTH on bones has yet to be elucidated in detail. Recently, some reports have demonstrated the crucial role of bone vasculature with regard to bone density. Angiopoietin-1 (Ang-1), along with VEGF, has been established as a primary angiogenic regulatory agent. In this study, we have attempted to characterize the effects of PTH (1-34) on Ang-1 expression and signaling molecules, employing primary-cultured human osteoblast-like cells. Quiescent osteoblasts were exposed to PTH (1-34), after which Ang-1 expression was determined at the mRNA and protein levels. Reverse transcription-polymerase chain reaction (RT-PCR) analyses indicated that Ang-1 mRNA expression increased as the result of PTH (1-34) treatment. The expression of the Ang-1 protein was also augmented as the result of treatment with PTH (1-34). An adenylyl cyclase activator, forskolin, was shown to induce Ang-1 mRNA expression, whereas the protein kinase A inhibitor, H-89, blocked the PTH (1-34)-mediated expression of Ang-1 mRNA. These findings indicate that PTH (1-34)-mediated Ang-1 expression involves adenylyl cyclase-protein kinase A dependent signaling. Our observations also show that Ang-1 may perform a crucial role in the effects of PTH (1-34) on bones, possibly involving alterations in bone vasculature.
Exp Clin Endocrinol Diabetes 2006 Sep
PMID:Parathyroid hormone (1-34) augments angiopoietin-1 expression in human osteoblast-like cells. 1703 26

Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, but only a small fraction of implanted islets become engrafted. The underlying mechanisms remain elusive. To probe the mechanism of islet revascularization, we determined the effect of angiopoietin-1 (Ang-1), a proangiogenic and antiapoptotic factor, on the survival, function, and revascularization of transplanted islets using a syngeneic model. Islets were transduced with adenoviruses expressing Ang-1 or control LacZ, followed by transplantation under the renal capsule. Diabetic mice receiving a marginal mass of 150 islets pretransduced with Ang-1 vector exhibited near normoglycemia posttransplantation. In contrast, diabetic mice receiving an equivalent islet mass pretransduced with control vector remained hyperglycemic. At 30 days posttransplantation, mice were killed and islet grafts retrieved for immunohistochemistry. Islet grafts with elevated Ang-1 production retained significantly increased microvascular density, improved glucose profiles, and increased glucose-stimulated insulin release. Cultured islets expressing Ang-1 displayed improved viability and enhanced glucose-stimulated insulin secretion in the presence of cytokines. In contrast, control islets exhibited increased apoptosis and diminished glucose-stimulated insulin release in response to cytokine treatment. These results indicate that Ang-1 confers a cytoprotective effect on islets, enhancing islet engraftment and preserving functional islet mass in transplants.
Diabetes 2007 Sep
PMID:Angiopoietin-1 production in islets improves islet engraftment and protects islets from cytokine-induced apoptosis. 1759 3

Pericytes are distinctive regulators of angiogenesis and are adumbrated to provide vessel stability and control of endothelial proliferation. The present article spotlights the persona of pericytes in physiological angiogenesis, recruitment of pericytes and different mechanisms of pericyte depletion. Developing retina appears particularly dependent on pericytes, and pericyte loss is considered as hallmark of early diabetic retinopathies. Several factors are contemplated to be engaged in pericyte conscription including angiopoietin-1 and its receptor tyrosine kinase Tie-2, vascular endothelial growth factor-A and its receptor flk-1 and the platelet-derived growth factor PDGF-B/PDGF-beta system. At present, the mechanisms by which diabetes persuade apoptosis in the retinal microvasculature remain indecisive, albeit oxidative stress, formation of advanced glycation end products , upregulation of protein kinase C, increased polyol pathway flux and focal leukostasis may be important. In this context, accelerated microvascular cell death may become a constructive surrogate end-point in pharmacological studies of experimental diabetic.
Diabetes Obes Metab 2008 Jan
PMID:Importance of pericytes and mechanisms of pericyte loss during diabetes retinopathy. 1794 74


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