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)

The effect of type 1 diabetes on bone healing and bone formation in standardized craniotomy defects created in BALB/cByJ mice was determined. The hypothesis that advanced glycation end products (AGEs) contribute to diminished bone healing in diabetes was evaluated by assessing for the presence of the receptor for advanced glycation end products (RAGE) by immunohistochemistry in healing craniotomy defects in diabetic animals. The effect of local application of a known RAGE protein ligand, N(epsilon)-(carboxymethyl)lysine (CML)-mouse serum albumin (MSA), on craniotomy defect healing in normal animals was then assessed and compared to the effects of control MSA. Finally, evidence in support of the expression of RAGE mRNA and protein in osteoblastic cells was obtained. The results indicated that craniotomy defects in diabetic animals healed approximately 40% of the degree to which they healed in nondiabetic animals (P < 0.05). RAGE was expressed at higher levels in healing bone tissues in diabetic compared to control animals. Further studies in nondiabetic animals indicated that bone healing was reduced by 63 and 42% in lesions treated with 900 and 90 micro g CML-MSA, respectively, compared to in animals treated with MSA alone (P < 0.05). Evidence for the expression of RAGE was obtained in mouse and rat osteoblastic cultures. These results support the contribution of AGEs to diminished bone healing in type 1 diabetes, possibly mediated by RAGE.
Diabetes 2003 Jun
PMID:A role for advanced glycation end products in diminished bone healing in type 1 diabetes. 1276 63

As is diabetes itself, diabetic vasculopathy is a multifactor disease. Studies revealed advanced glycation end products (AGE) as the major environmental account for vascular cell derangement characteristic of diabetes and the receptor for AGE (RAGE) as the major genic factor that responds to them. AGE fractions that caused the vascular derangement were proved to be RAGE ligands. When made diabetic, RAGE transgenic mice exhibited the exacerbation of the indices of nephropathy and retinopathy, and this was prevented by the inhibition of AGE formation. Extracellular signals and nuclear factors that induce the transcription of human RAGE gene were also identified, which would be regarded as risk factors of diabetic complications. Through an analysis of vascular polysomal poly(A)(+)RNA, a novel splice variant coding for a soluble RAGE protein was found and was named endogenous secretory RAGE. Endogenous secretory RAGE was able to capture AGE ligands and to neutralize the AGE action on endothelial cells, suggesting that this variant has a potential to protect blood vessels from diabetes-induced injury. The AGE-RAGE system, therefore, should be a candidate molecular target for overcoming this life- and quality-of-life-threatening disease.
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PMID:The AGE-RAGE system and diabetic nephropathy. 1287 43

A leading theory of the pathophysiology of preeclampsia is that oxidative stress induces vascular endothelial cell dysfunction. Advanced glycation end products (AGEs) form when aldose sugars react nonenzymatically with proteins under conditions of oxidative stress. AGEs are circulating molecules and can generate reactive oxygen species and vascular dysfunction (in diabetes and atherosclerosis) through an association with cell surface receptors (RAGE). RAGE is a multiligand receptor, expressed in vascular tissue, which is upregulated by its own ligands. Insulin resistance and obesity are risk factors for developing preeclampsia, as well as being conditions that would increase RAGE levels. Thus, we hypothesized that women with preeclampsia will have elevated levels of RAGE protein compared with normal pregnant women. Biopsies of nonlaboring myometrium as well as omentum were taken from normal pregnant and preeclamptic women. Nonpregnant samples were obtained at the time of hysterectomy. Tissue sections were immunostained with anti-RAGE as well as anti-alpha-actin and anti-von Willebrand factor (to identify blood vessels and intact endothelial cells). Staining intensity was qualitatively described as well as given an intensity score, with the identity of the section concealed. Nonpregnant myometrial and omental vessels showed very low to undetectable levels of RAGE staining. Pregnancy induced a significant increase in RAGE protein levels in both myometrium and omental vasculature. Blood vessels from women with preeclampsia consistently had intense staining for RAGE in both vessel beds. Thus, our data suggest that since RAGE activation can induce similar pathophysiologic changes to those observed in women with preeclampsia (including NFkappaB activation, increased TNFalpha and endothelin), elevated RAGE protein may be contributing to the vascular dysfunction in preeclampsia.
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PMID:The receptor for advanced glycation end products (RAGE) is elevated in women with preeclampsia. 1290 2

Diabetic patients have shorter life span and poorer Quality of Life mainly due to diabetic vascular complications. Recent in vitro and in vivo studies have shown that advanced glycation endproducts (AGE) account for diabetic vascular complications through their engagement of the receptor for AGE (RAGE). In this review, we summarize our recent studies on the roles of the AGE-RAGE system in diabetes-induced vascular injury. In vitro experiments showed that AGE engagement of RAGE leads to changes in endothelial cells (EC) and pericytes, which are characteristic of diabetic microangiopathy. Diabetic RAGE transgenic mice that overexpress RAGE in vascular cells exhibited the exacerbation of the indices of nephropathy and retinopathy, and this was prevented by the inhibition of AGE formation. RAGE overexpression also caused calcium handling impairment in cardiac myocytes. In contrast to the RAGE-overexpressing mice, diabetic RAGE knockout mice showed marked improvement of nephropathy. We found that human vascular cells express a novel splice variant coding for a soluble RAGE protein and named it endogenous secretory RAGE (esRAGE). The esRAGE neutralizes AGE actions on EC and is present in human sera. Individual variations in circulating esRAGE could be a determinant for individual differences in susceptibility or resistance to the development of diabetic vascular complications. The AGE-RAGE system should be, therefore, a candidate molecular target for overcoming diabetic vascular complications.
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PMID:Roles of the receptor for advanced glycation endproducts in diabetes-induced vascular injury. 1575 Feb 91

Recent studies have identified that first-line renoprotective agents that interrupt the renin-angiotensin system not only reduce BP but also can attenuate advanced glycation end product (AGE) accumulation. This study used in vitro, preclinical, and human approaches to explore the potential effects of these agents on the modulation of the receptor for AGE (RAGE). Bovine aortic endothelial cells that were exposed to the angiotensin-converting enzyme inhibitor (ACEi) ramiprilat in the presence of high glucose demonstrated a significant increase in soluble RAGE (sRAGE) secreted into the medium. In streptozotocin-induced diabetic rats, ramipril treatment (ACEi) at 3 mg/L for 24 wk reduced the accumulation of skin collagen-linked carboxymethyllysine and pentosidine, as well as circulating and renal AGE. Renal gene upregulation of total RAGE (all three splice variants) was observed in ACEi-treated animals. There was a specific increase in the gene expression of the splice variant C-truncated RAGE (sRAGE). There were also increases in sRAGE protein identified within renal cells with ACEi treatment, which showed AGE-binding ability. This was associated with decreases in renal full-length RAGE protein from ACEi-treated rats. Decreases in plasma soluble RAGE that were significantly increased by ACEi treatment were also identified in diabetic rats. Similarly, there was a significant increase in plasma sRAGE in patients who had type 1 diabetes and were treated with the ACEi perindopril. Complexes between sRAGE and carboxymethyllysine were identified in human and rodent diabetic plasma. It is postulated that ACE inhibition reduces the accumulation of AGE in diabetes partly by increasing the production and secretion of sRAGE into plasma.
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PMID:Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy. 1597 94

Advanced glycation end products (AGEs) and the receptor for AGE (RAGE) interactions have been implicated in the development of diabetic vascular complications, which cause various disabilities and shortened life expectancy, and reduced quality of life in patients with diabetes. Diabetes-induced RAGE-overexpressing transgenic mice exhibited the exacerbation of the indices of nephropathy, and this was prevented by the inhibition of AGE formation. We also created RAGE-deficient mice by homologous recombination. They showed marked amelioration of diabetic nephropathy as compared with wild-type mice. Through an analysis of vascular polysomal poly(A)+ RNA, we identified a novel splice variant coding for a soluble RAGE protein and named it endogenous secretory RAGE (esRAGE). esRAGE was able to protect AGE-induced vascular cell injuries as a decoy receptor and was actually detected in human circulation. We conclude that RAGE plays an active role in the development of diabetic vascular complications, especially nephropathy, and is a promising target for overcoming this disease. The esRAGE, an endogenous decoy receptor, may be related to individual variations in resistance to the development of diabetic vascular complications.
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PMID:Receptor for advanced glycation end products is a promising target of diabetic nephropathy. 1603 79

The receptor for advanced glycation end products (RAGE) and the angiotensin II type I receptor (AT1R) have been separately linked to the pathogenesis of diabetic atherosclerosis. However, no prior study has addressed a linkage between RAGE and AT1R in diabetic atherogenesis. Therefore, we tested the hypothesis that upregulation of the ligand-RAGE axis via AT1R is an essential process underlying the disease. Diabetes was induced in apolipoprotein E-deficient (ApoE(-/-)) mice by streptozotocin, and diabetic mice were treated with AT1 receptor blocker (ARB) for 6 weeks. Diabetic ApoE(-/-) mice that were AT1R-deficient (ApoE(-/-)AT1aR(-/-)) were also investigated. In diabetic ApoE(-/-) mice, AT1R was found to increase within 1 week of diabetes induction, before ligand-RAGE pathway activation and other inflammatory changes were observed. Both ARB treatment and AT1aR deficiency suppressed diabetic atherosclerosis, ligand-RAGE expression and inflammatory changes. In contrast, upregulation of the ligand-RAGE pathway was noted in atherosclerotic plaques from non-diabetic ApoE(-/-) mice infused with angiotensin II. In cultured vascular smooth muscle cells, angiotensin II increased RAGE protein levels via AT1R stimulation. Upregulation of the ligand-RAGE pathway via AT1R is an essential mechanism in diabetic atherosclerosis, implying that ARB might decrease diabetic atherogenesis by inhibiting ligand-RAGE signals.
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PMID:Upregulation of the ligand-RAGE pathway via the angiotensin II type I receptor is essential in the pathogenesis of diabetic atherosclerosis. 1776 Nov 93

Advanced glycation endproducts (AGEs) are implicated in the complications of diabetes and ageing, affecting several tissues, including bone. Metformin, an insulin-sensitizer drug, reduces the risk of life-threatening macrovascular complications. We have evaluated the hypothesis that metformin can abrogate AGE-induced deleterious effects in osteoblastic cells in culture. In two osteoblast-like cell lines (UMR106 and MC3T3E1), AGE-modified albumin induced cell death, caspase-3 activity, altered intracellular oxidative stress and inhibited alkaline phosphatase activity. Metformin-treatment of osteoblastic cells prevented these AGE-induced alterations. We also assessed the expression of AGE receptors as a possible mechanism by which metformin could modulate the action of AGEs. AGEs-treatment of osteoblast-like cells enhanced RAGE protein expression, and this up-regulation was prevented in the presence of metformin. Although the precise mechanisms involved in metformin signaling are still elusive, our data implicate the AGE-RAGE interaction in the modulation of growth and differentiation of osteoblastic cells.
Exp Clin Endocrinol Diabetes 2008 Jun
PMID:Metformin reverts deleterious effects of advanced glycation end-products (AGEs) on osteoblastic cells. 1827 53

The receptor for advanced-glycation-end-products (RAGE) has been implicated as a pro-inflammatory factor in chronic inflammatory conditions such as diabetes mellitus and rheumatoid arthritis. The aim of this study was to investigate the inhibitory effect of the soluble-RAGE (sRAGE), the extracellular domain of RAGE, on RAGE expression and NF-kappaB translocation in human-salivary gland-cell-lines (HSG). Cells were stimulated with agonist S100A4, fusion protein of RAGE encompassing the extracellular domain of RAGE (ex-RAGE), ex-RAGE followed by S100A4, or S100A4 followed by ex-RAGE. Our study indicates that RAGE expression was highest at 150 microg/microl of S100A4 and efficiently down-regulated by 1.8-fold (P < 0.05) when ex-RAGE was incubated prior to agonist S100A4. RAGE protein was also consistently down-regulated by 20-40% with pre-incubation of ex-RAGE. More importantly, nuclear translocation of p65 and p52 of NF-kappaB by S100A4 was inhibited in the presence of ex-RAGE, confirming anti-inflammatory function of ex-RAGE. In conclusion, ex-RAGE down-regulates RAGE expression and inhibits p65 and p52 activation in HSG, providing evidence that ex-RAGE functions as a "decoy" to RAGE-ligand interaction and thus potentially dampening inflammatory conditions.
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PMID:RAGE expression and NF-kappaB activation attenuated by extracellular domain of RAGE in human salivary gland cell line. 1959 Nov 73

Endothelial progenitor cells (EPCs) play an important role in preventing atherosclerosis. The factors that regulate the function of EPCs are not completely clear. Increased formation of advanced glycation endproducts (AGEs) is generally regarded as one of the main mechanisms responsible for vascular damage in patients with diabetes and atherosclerosis. AGEs lead to the generation of reactive oxygen species (ROS) and part of the regenerative capacity of EPCs seems to be due to their low baseline ROS levels and reduced sensitivity to ROS-induced cell apoptosis. Therefore, we tested the hypothesis that AGEs can alter functions and promote apoptosis in EPCs through overpress cell oxidant stress. EPCs, isolated from bone marrow, were cultured in the absence or presence of AGEs (50, 100, and 200 microg/ml). A modified Boyden's chamber was used to assess the migration of EPCs and the number of recultured EPCs was counted to measure the adhesiveness function. MTT assay was used to determine the proliferation function. ROS were analyzed using the ROS assay kit. A spectrophotometer was used to assess superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity, and PCR was used to test mRNA expression of SOD and GSH-PX. SiRNA was used to block receptor for advanced glycation endproducts (RAGEs) expression. Apoptosis was evaluated by Annexin V immunostaining and TUNEL staining. Co-culturing with AGEs increases ROS production, decreases anti-oxidant defenses, overpresses oxidant stress, inhibits the proliferation, migration, and adhesion of EPCs, and induces EPCs apoptosis. In addition, these effects were attenuated during block RAGE protein expression by siRNA. AGEs may serve to impair EPCs functions through RAGE-mediate oxidant stress, and promote EPCs sensitivity toward oxidative-stress-mediated apoptosis, which indicates a new pathophysiological mechanism of disturbed vascular adaptation in atherosclerosis and suggests that lower levels of AGEs might improve the success of progenitor cell therapy.
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PMID:Advanced glycation endproducts alter functions and promote apoptosis in endothelial progenitor cells through receptor for advanced glycation endproducts mediate overpression of cell oxidant stress. 1975 58


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