UMLS:C0011881 - FACTA Search

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Query: UMLS:C0011881 (diabetic nephropathy)
10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetic nephropathy often co-exists with other manifestations of microangiopathy, in particular retinopathy. Recent clinical evidence suggests that inhibition of the renin-angiotensin system in humans can delay the development and/or progression of diabetic nephropathy and perhaps also retinopathy. The benefits of this therapeutic strategy may in part be explained by inhibition of the nonhaemodynamic actions of angiotensin II (Ang II). The recognized nonhaemodynamic actions of Ang II include the augmented release of many growth factors. Ang II can stimulate the release of vascular endothelial growth factor (VEGF) from human vascular tissues. VEGF is a family of potent cytokines which act to induce angiogenesis and markedly increase microvascular permeability. VEGF is abundantly expressed in the renal glomerulus, specifically within the podocyte, where its function is unknown. VEGF is also expressed in the retina and increased retinal VEGF expression occurs in diabetes and has been implicated in the pathogenesis of diabetic retinopathy. This review considers the potential clinical significance of Ang II-induced VEGF expression, if any, in the pathogenesis of diabetic nephropathy and retinopathy.
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PMID:A potential role for angiotensin II-induced vascular endothelial growth factor expression in the pathogenesis of diabetic nephropathy? 993 Mar 79

The development of diabetic nephropathy in patients with Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus is still a huge clinical problem associated with increased morbidity and mortality. The mechanisms underlying the development of diabetic kidney disease are extremely complex and yet not completely understood. Among many potential pathogenic mechanisms responsible for the development of diabetic kidney disease, various growth factors have been suggested to be important players. In particular, growth hormone (GH)/insulin-like growth factors (IGFs), transforming growth factor beta (TGF-beta), vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) have measurable effects on the development of experimental diabetic kidney disease through complex intra-renal systems. Recent findings that these growth factors might initiate the early diabetic renal changes have provided insight into processes that might be relevant for future development of new drugs useful in the treatment of diabetic kidney disease. As will appear from the present review, enhanced understanding of the cellular mechanisms responsible for the development of diabetic kidney disease has already allowed the design of specific antagonists of pathophysiologically increased growth factors. Recent studies have shown that treating experimental diabetic models with such antagonists is followed by renoprotection.
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PMID:Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease. 1107 38

This study was designed to evaluate whether vascular endothelial growth factor serum concentrations may identify adolescents with onset of type 1 diabetes during childhood at greater risk to develop persistent microalbuminuria and incipient diabetic nephropathy. In January 1989, vascular endothelial growth factor serum levels were measured in 101 normoalbuminuric diabetic children and adolescents (aged 7-14.9 yr; onset of diabetes before age 18 yr; duration of diabetes >7 yr). Participants were clinically examined at baseline and annually thereafter. Vascular endothelial growth factor serum concentrations were measured every year during the 8-yr follow-up period. Over 8 yr, 11 of 101 patients (10.9%) developed persistent microalbuminuria; no patient developed overt nephropathy. The risk of developing microalbuminuria was higher in children with increased vascular endothelial growth factor serum levels (using 160 pg/ml as the arbitrary cut-off point; group 1) compared with those with normal vascular endothelial growth factor serum levels at the beginning of the study (group 2; 19.2 vs. 2.0%; P < 0.01; sensitivity, 90.9%; specificity, 53.3%). The odds ratio for the occurrence of microalbuminuria after adjustment for confounding variables (albumin excretion rate, sex, hemoglobin A(1c), mean blood pressure, cholesterol, and triglycerides) in type 1 diabetic adolescents with elevated vascular endothelial growth factor serum levels was 4.1 (95% confidence interval, 2.0-10.9). These results suggest that vascular endothelial growth factor serum concentrations may be one of the predictors and risk factors for microalbuminuria and incipient diabetic nephropathy in adolescents and young adults with onset of diabetes during childhood. Persistently increased vascular endothelial growth factor serum levels may help to identify normotensive, normoalbuminuric patients with type 1 diabetes who are predisposed to develop persistent microalbuminuria later in life.
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PMID:Increased vascular endothelial growth factor serum concentrations may help to identify patients with onset of type 1 diabetes during childhood at risk for developing persistent microalbuminuria. 1150 26

Diabetic nephropathy is the leading cause of end-stage renal disease worldwide. Although death rates of diabetic patients on hemodialysis and peritoneal dialysis (PD) have decreased substantially, they remain higher than rates in nondiabetics on both modalities. PD offers equal or better survival than hemodialysis for younger diabetic patients during early years of dialysis. PD technique survival does not appear different between diabetic and nondiabetic patients but is inferior to hemodialysis technique survival. PD may accelerate changes in peritoneal membrane structure and function in diabetics. Peritonitis and conventional PD solutions containing high glucose and glucose degradation products are implicated in PD technique failure. Increased peritoneal expression of vascular endothelial growth factor and transforming growth factor-beta1 and excessive accumulation of advanced glycosylation end products may be involved in the progressive increase in membrane permeability, loss of ultrafiltration, and peritoneal fibrosis. Nonglucose PD solutions or solutions containing low glucose degradation products may prevent or delay alterations in peritoneal membrane structure and function in diabetic as well as nondiabetic patients during long-term PD.
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PMID:Peritoneal dialysis in diabetic patients. 1157 55

Podocytes are the major site of vascular endothelial growth factor (VEGF) production in the kidney, and up-regulation of VEGF plays a critical role in the progression of diabetic nephropathy. Using a differentiated mouse podocyte cell line, we investigated the roles of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) on the expression of VEGF under high glucose conditions. High glucose induced up-regulation of VEGF mRNA and protein expression in podocytes via activation of PKC (PKC-alpha and -betaII isoforms) and ERK. High glucose stimulated [(3)H]leucine incorporation in the podocytes. High glucose and the PKC stimulator, phorbol 12-myristate 13-acetate (PMA) induced activator protein-1 (AP-1)-dependent transcriptional activity and expression of VEGF. In addition, these phenomena were blocked by specific inhibitors of PKC (GF10902X) and ERK kinase (PD98059). These observations suggested that high glucose-induced VEGF expression in podocytes was largely mediated through PKC and ERK pathways that may be involved in diabetic nephropathy.
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PMID:High glucose induced VEGF expression via PKC and ERK in glomerular podocytes. 1177 50

The zucker diabetic fatty (ZDF-fa/fa) rat is one of the attractive models for type II diabetes based on impaired glucose tolerance caused by the inherited insulin-resistance gene fa. Characterization of nephropathy in this model may provide useful insights into the mechanism of the progression of diabetic nephropathy. The present study analyzed the pathophysiology of diabetes and nephropathy, including the process of glomerulosclerosis in this model by biochemical and morphometric analyses. In addition, we conducted studies in podocytes in culture to examine the direct effects of high glucose on podocytes. ZDF-fa/fa rats showed overt diabetes despite hyperinsulinemia as early as 3 months of age. Blood glucose levels increased further with a considerable decrease of insulin levels at 5 months. Glomerular filtration rate (GFR) was significantly elevated until 3 months, but fell to the level seen in lean rats by 7 months. Proteinuria started to rise during the period of increased GFR, and increased further after GFR had fallen to within the normal range. Renal fibronectin, collagen iv, and vascular endothelial growth factor mRNA levels were increased at 7 months. Glomerulosclerosis commenced as early as 5 months of age, and was associated with glomerular hypertrophy and mild mesangial expansion with evidence of accentuated podocyte injury, as revealed by increased expression of desmin. Electron microscopy suggested that degeneration of podocytes and the development of tuft adhesions were responsible for the glomerular sclerosis in this model. In addition, glomeruli from the diabetic rats showed up-regulation of the cyclin kinase inhibitors, p21 and p27. Further studies suggested that the increase in p27 expression was predominantly caused by podocytes, because predominant immunolocalization of p27 in podocytes in diabetic rats and high glucose medium induced cell hypertrophy accompanied by p27 up-regulation in differentiated podocyte cell lines. In conclusion, progressive diabetic nephropathy in ZDF-fa/fa rats is associated with evidence of podocyte injury. High concentrations of ambient glucose induced podocyte hypertrophy and stress in vitro, suggesting that the podocyte is a likely target of the diabetic milieu.
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PMID:Podocyte injury promotes progressive nephropathy in zucker diabetic fatty rats. 1179 23

Diabetic renal disease is associated with lipid deposits in the kidney. The purpose of our study was to determine whether there is altered regulation of the sterol regulatory element-binding proteins (SREBPs) in the diabetic kidney and whether SREBPs mediate the abnormal renal lipid metabolism and diabetic renal disease. In streptozotocin-induced diabetes in the rat, there were marked increases in SREBP-1 and fatty acid synthase (FAS) expression, resulting in increased triglyceride (TG) accumulation. Treatment of diabetic rats with insulin prevented the increased renal expression of SREBP-1 and the accumulation of TG. The role of hyperglycemia in the up-regulation of SREBP-1 was confirmed in renal cells cultured in a high glucose media. High glucose induced increased expression of SREBP-1a and -1c mRNA, SREBP-1 protein, and FAS, resulting in increased TG content. To determine a direct role for SREBP in mediating the increase in renal lipids and glomerulosclerosis, we studied SREBP-1a transgenic mice with increased renal expression of SREBP-1. The increase in SREBP-1 was associated with increased expression of FAS and acetyl CoA carboxylase, resulting in increased TG content, increased expression of transforming growth factor beta1 and vascular endothelial growth factor, mesangial expansion, glomerulosclerosis, and proteinuria. Our study therefore indicates that renal SREBP-1 expression is increased in diabetes and that SREBP-1 plays an important role in the increased lipid synthesis, TG accumulation, mesangial expansion, glomerulosclerosis, and proteinuria by increasing the expression of transforming growth factor beta and vascular endothelial growth factor.
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PMID:Role of sterol regulatory element-binding protein 1 in regulation of renal lipid metabolism and glomerulosclerosis in diabetes mellitus. 1187 60

Advanced glycation end products (AGE) have been implicated in the pathogenesis of glomerulosclerosis in diabetes. However, their involvement in the development of the early phase of diabetic nephropathy has not been fully elucidated. We investigated the effects of AGE on growth and on vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) expression in human cultured mesangial cells. We prepared three immunochemically distinct AGE by incubating bovine serum albumin (BSA) with glucose, glyceraldehyde, or glycolaldehyde. When human mesangial cells were cultured with various types of AGE-BSA, viable cell numbers as well as DNA syntheses were significantly decreased. All of the AGE-BSA were found to significantly increase p53 and Bax protein accumulations and subsequently induce apoptotic cell death in mesangial cells. An antioxidant, N-acetylcysteine, significantly prevented the AGE-induced apoptotic cell death in mesangial cells. Human mesangial cells stimulated prostacyclin production by co-cultured glomerular endothelial cells. Furthermore, various types of AGE-BSA were found to up-regulate the levels of mRNAs for VEGF and stimulate the secretion of VEGF and MCP-1 proteins in mesangial cells. The results suggest that AGE disturbed glomerular homeostasis by inducing apoptotic cell death in mesangial cells and elicited hyperfiltration and microalbuminuria by stimulating the secretion of VEGF and MCP-1 proteins, thereby being involved in the pathogenesis of the early phase of diabetic nephropathy.
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PMID:Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells. 1191 19

Diabetic nephropathy in type 2 diabetic patients is a frequent complication associated with increased morbidity and mortality. Various growth factors and cytokines have been implicated in the pathogenesis of diabetic kidney disease, including vascular endothelial growth factor (VEGF). To explore a role for VEGF in renal changes in type 2 diabetes, we examined the renal effects of a neutralizing murine VEGF antibody in the diabetic db/db mouse, a model of obese type 2 diabetes. One group of db/db mice was treated for 2 months with a VEGF antibody, while another db/db group was treated for the same period with an isotype-matched irrelevant IgG. A third group consisting of nondiabetic db/+ mice was treated with the same isotype-matched IgG for 2 months. Placebo-treated db/db mice showed a pronounced increase in kidney weight, glomerular volume, basement membrane thickness (BMT), total mesangial volume, urinary albumin excretion (UAE), and creatinine clearance (CrCl) when compared with nondiabetic controls. In VEGF antibody-treated db/db mice, increases in kidney weight, glomerular volume, BMT, and UAE were attenuated, whereas the increase in CrCl was abolished. VEGF antibody administration tended to reduce expansion in total mesangial volume. These effects in diabetic animals were seen without impact on body weight, blood glucose, insulin levels, or food consumption. In conclusion, chronic inhibition of VEGF in db/db mice ameliorates the diabetic renal changes seen in type 2 diabetes.
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PMID:Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody. 1235 52

There is increasing evidence implicating genetic factors in the susceptibility to diabetic microvascular complications. Recent studies suggest that increased expression of the cytokine vascular endothelial growth factor (VEGF) may play a role in the pathogenesis of diabetic complications. A number of polymorphisms in the promoter region of the VEGF gene have been identified. The aim was to investigate whether an 18 base pair (bp) deletion (D)/insertion (I) polymorphism at position -2549 in the promoter region of the VEGF gene is associated with the susceptibility to diabetic microvascular complications. Two hundred and thirty-two patients with type 1 diabetes mellitus (T1DM) and 141 normal healthy controls were studied. The D/D genotype was significantly increased in those patients with nephropathy (n=102) compared to those with no complications after 20 years duration of diabetes (uncomplicated, n=66) (40.2% vs. 22.7%, respectively, chi(2)=5.5, P<.05). The combination of polymorphisms of VEGF together with the aldose reductase (ALR2) gene showed that in the nephropaths, 8 of the 83 subjects had the VEGF I allele together with the Z+2 5'ALR2 allele compared with 27 of the 62 uncomplicated patients (chi(2)=26.7, P<.00001). The functional role of the D/I polymorphism was examined by cloning the region into a luciferase reporter assay system and transient transfection into HepG2 cells. The construct containing the 18 bp deletion had a 1.95-fold increase in transcriptional activity compared with its counterpart that had the insert (P<.01). These results suggest that polymorphisms in the promoter region of the VEGF gene together with the ALR2 may be associated with the pathogenesis of diabetic nephropathy.
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PMID:Polymorphisms of the vascular endothelial growth factor and susceptibility to diabetic microvascular complications in patients with type 1 diabetes mellitus. 1250 48

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