Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that maintains the glomerular and peritubular capillary (PTC) network in the kidney. The soluble form of the VEGF receptor-1 (soluble fms-like tyrosine kinase 1 (sFlt-1)) is known to regulate VEGF activity by binding VEGF in the circulation. We hypothesized that VEGF may be beneficial for maintaining glomerular filtration barrier and vascular network in rats with progressive glomerulonephritis (GN). For blockade of VEGF activity in vivo, rats were transfected twice with plasmid DNA encoding the murine sFlt-1 gene into femoral muscle 3 days before and 2 weeks after the induction of antiglomerular basement membrane antibody-induced GN. Inhibition of VEGF with sFlt-1 resulted in massive urinary protein excretion, concomitantly with downregulated expression of nephrin in nephritic rats. Further, blockade of VEGF induced mild proteinuria in normal rats. Administration of sFlt-1 affected neither the infiltration of macrophages nor crescentic formation. In contrast, treatment of sFlt-1 accelerated the progression of glomerulosclerosis and interstitial fibrosis accompanied with renal dysfunction and PTC loss at day 56. VEGF may play a role in maintaining the podocyte function as well as renal vasculature, thereby protecting glomeruli and interstitium from progressive renal insults.
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PMID:Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis. 1664 24

Vascular endothelial growth factor (VEGF) is an important mediator in maintaining normal kidney functions. In addition, several lines of evidence suggest that upregulation of VEGF in glomeruli may be associated with or cause renal dysfunction such as diabetic nephropathy. For elucidation of the pathologic consequences of high levels of VEGF in glomeruli, transgenic (Tg) rabbits that express human VEGF(165) isoform in both kidney and liver under the control of the human alpha-1-antitrypsin promoter were generated and characterized. With the use of heterozygous Tg rabbits and their littermates aged 8 to 55 wk, renal functions and structures were investigated. Compared with control rabbits, Tg rabbits exhibited progressive proteinuria with increased GFR at the early stage and decreased GFR at the later stage. Histologic examinations revealed that Tg rabbit kidneys were characterized by considerable glomerular hypertrophy as a result of increased proliferation of both glomerular capillaries and mesangial cells accompanied by prominent podocyte hypertrophy. With increasing age starting from 20 wk, Tg rabbit kidneys showed prominent formation of microaneurysms and capillary proliferation at the vascular pole area. At a later stage (55 wk), many glomeruli showed sclerosis and tuft collapse with the formation of glomerular cysts on a background of tubular atrophy and interstitial fibrosis. This study provides the first evidence that increased expression of VEGF in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria, suggesting that VEGF exerts multiple effects on the glomerular pathophysiologic processes.
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PMID:Increased expression of vascular endothelial growth factor in kidney leads to progressive impairment of glomerular functions. 1755 51

Vascular endothelial growth factor (VEGF) is implicated in the development of proteinuria in diabetic nephropathy. High ambient glucose present in diabetes stimulates VEGF expression in several cell types, but the molecular mechanisms are incompletely understood. Here primary cultured rat mesangial cells served as a model to investigate the signal transduction pathways involved in high-glucose-induced VEGF expression. Exposure to high glucose (25 mM) significantly increased VEGF mRNA evaluated by real-time PCR by 3 h, VEGF cellular protein content assessed by immunoblotting or immunofluorescence within 24 h, and VEGF secretion by 24 h. High-glucose-induced VEGF expression was blocked by an antioxidant, Tempol, and antisense oligonucleotides directed against p22(phox), a NADPH oxidase subunit. Inhibition of protein kinase C (PKC)-beta(1) with the specific pharmacological inhibitor LY-333531 or inhibition of PKC-zeta with a cell permeable specific pseudosubstrate peptide also prevented enhanced VEGF expression in high glucose. Enhanced VEGF secretion in high glucose was prevented by Tempol, PKC-beta(1), or PKC-zeta inhibition. In normal glucose (5.6 mM), overexpression of p22(phox) or constitutively active PKC-zeta enhanced VEGF expression. Hypoxia inducible factor-1alpha protein was significantly increased in high glucose only by 24 h, suggesting a possible contribution to high-glucose-stimulated VEGF expression at later time points. Thus reactive oxygen species generated by NADPH oxidase, and both PKC-beta(1) and -zeta, play important roles in high-glucose-stimulated VEGF expression and secretion by mesangial cells.
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PMID:Reactive oxygen species, PKC-beta1, and PKC-zeta mediate high-glucose-induced vascular endothelial growth factor expression in mesangial cells. 1771 90

Vascular endothelial growth factor (VEGF) plays a key role in the development of both proliferative diabetic retinopathy (PDR) and diabetic macular oedema (DMO). In recent years, anti-VEGF agents have emerged as new approaches to the treatment of these devastating diabetic complications. Although Phase III studies in the diabetic population are needed, intravitreal anti-VEGF therapy is currently being used in clinical practice. Intravitreal injection is an effective means of delivering anti-VEGF drugs to the retina. However, this is an invasive procedure associated with potentially serious complications, such as endophthalmitis or retinal detachment, which may be significant for patients requiring serial treatment over many years. In addition, although delivered within the vitreous, anti-VEGF drugs could pass into the systemic circulation, which could potentially result in hypertension, proteinuria, increased cardiovascular events and impaired wound healing. Pegaptanib, ranibizumab and bevacizumab are the currently available anti-VEGF agents. Ranibizumab and bevacizumab block all VEGF isoforms, thus impairing both physiological and pathological neovascularisation. Pegaptanib only blocks the VEGF(165) isoform, and would therefore seem the best option for avoiding systemic adverse effects in diabetic patients, although this remains to be demonstrated in clinical trials. In this regard, head-to-head studies designed to evaluate not only the efficacy, but also the systemic adverse effects of these drugs in a high-risk population such as diabetic patients are warranted.
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PMID:Intravitreous anti-VEGF for diabetic retinopathy: hopes and fears for a new therapeutic strategy. 1860 60

Vascular endothelial growth factor receptor-1 (VEGFR-1) is essential for the normal development and function of the placenta. Defective placental vasculogenesis and trophoblast function may lead to pre-eclampsia, a pregnancy-specific syndrome of hypertension and proteinuria. In order to study the association of VEGFR-1 with the development of pre-eclampsia, a cross-sectional study was carried out to evaluate the concentration of soluble VEGFR-1 (sVEGFR-1) in 360 serum samples and to analyze the expression of membranous VEGFR-1 in 40 placental samples of normal and pre-eclamptic pregnant women. Serum and placental samples at different gestational ages were collected from the Department of Obstetrics and Gynaecology, VMMC and Safdarjang Hospital, New Delhi. The serum levels of sVEGFR-1 and the expression of membranous VEGFR-1 were estimated by enzyme-linked immunosorbent assay and immunohistochemistry, respectively. The serum levels of sVEGFR-1 were seen to be positively increased (p=0.0001) in patients with pre-eclampsia at different gestational intervals as compared to the healthy pregnant women they were matched with. However, receiver operating characteristic (ROC) curve analysis showed a higher sensitivity (89.17%) and specificity (90.0%) in early onset (< or =34 weeks) in contrast with the late-onset (>34 weeks) pre-eclamptic group. Also, significant up-regulation of membranous VEGFR-1 immunoreactivity was observed in all placental cells (syncytiotrophoblast, cytotrophoblast, endothelial cells and Hofbauer cells) of pre-eclamptic groups in both < or =34 weeks (p=0.0001) and >34 weeks (p=0.0001) as compared to the normal group. Elevated sVEGFR-1 serum levels and up-regulated membranous VEGFR-1 expression in placenta denote abnormality in VEGF-mediated function in all placental cells, and thus may contribute to etiopathogenesis of pre-eclampsia. Nevertheless, this study also shows the possible diagnostic utility of sVEGFR-1 as a sensitive and specific biomarker for the early onset (< or =34 weeks) of pre-eclampsia.
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PMID:Soluble and membranous vascular endothelial growth factor receptor-1 in pregnancies complicated by pre-eclampsia. 1899 79

Low nephron endowment secondary to intrauterine growth restriction (IUGR) results in compensatory hypertrophy of the remaining glomeruli, which in turn is associated with hypertension. However, gender differences exist in the response of the kidney to injury, and IUGR female offspring seems protected from an unfavorable outcome. We previously reported differences in gender-specific gene expression in the IUGR kidney as well as increased circulating corticosterone levels following uteroplacental insufficiency (UPI). Vascular endothelial growth factor (VEGF), which is critical for renal development, is an important candidate in the IUGR kidney since its expression can be regulated by sex-steroids and glucocorticoids. We hypothesize that IUGR leads to altered kidney VEGF expression in a gender-specific manner. Following uterine ligation in the pregnant rat, UPI decreases renal VEGF levels in male and female IUGR animals at birth and through postnatal day 21. However, by day 120 of life, IUGR females have increased kidney VEGF expression, not present in the IUGR males. In addition, IUGR males exhibit increased serum testosterone levels as well as proteinuria. These findings are intriguing in light of the difference in glomerular hypertrophy observed: IUGR males show increased glomerular area when compared to IUGR females. In this model characterized by decreased nephron number and adult onset hypertension, UPI decreases renal VEGF expression during nephrogenesis. Our most intriguing finding is the increased renal VEGF levels in adult IUGR females, associated with a more benign phenotype. We suggest that the mechanisms underlying renal disease in response to IUGR are most likely regulated in a gender specific manner.
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PMID:Uteroplacental insufficiency affects kidney VEGF expression in a model of IUGR with compensatory glomerular hypertrophy and hypertension. 1918 30

The growth of new blood vessels, angiogenesis is important for tumour progression and metastasis. Vascular endothelial growth factor (VEGF) plays multiple roles in cancer development. Due to it the VEGF seems to be an optimal therapeutic target in breast cancer therapy. The plasma level of this growth factor is highest early in disease suggests that anti-VEGF agents may provide their greatest benefit in firts-line chemotherapy with metastatic breast cancer (MBC). A phase III trial, E2100 evaluated weekly paclitaxel with or without bevacizumab (Avastin), the specific humanised anti-VEGF monoclonal antibody in patients with previously untreated locally recurrent or MBC, doubling of progression-free survival for all patient subgroups. Bevacizumab is generally well tolerated. The most common adverse events observed in trials hypertension, proteinuria, and wound-healing complications, most of which are grade 1-2 in severity. The registration of bevacizumab for MBC therapy brings new hope for patients. Novel approach of bevacizumab for MBC would be combination chemotherapy and different targeted therapies. Phase III clinical trials of bevacizumab are ongoing in different stages in different settings.
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PMID:[Anti-VEGF therapy with bevacizumab in breast cancer]. 1922 9

Vascular endothelial growth factor (VEGF) is a main regulator of blood vessel growth and plays an important role in promoting endothelial survival and maintaining the microvasculature. The kidney is a highly vascularized organ and has two important microvasculatures; glomerular and peritubular capillaries. Loss of these capillaries is strongly associated with the progression of chronic kidney disease (CKD) to end-stage renal disease. In several kidney disease animal models, VEGF expression in the kidney is decreased and administration of VEGF is protective. Recent clinical observations revealed that blocking VEGF by endogenous inhibitor (soluble Flt-1) in preeclampsia and monoclonal antibody against VEGF in cancer patients cause proteinuria and renal dysfunction. However, plasma VEGF levels in diabetic nephropathy patients are increased and blocking VEGF improved diabetic nephropathy in animal models. Increased plasma VEGF levels have been reported in CKD patients. Deleterious effects of VEGF have been demonstrated in atherosclerosis and sepsis, which are frequent complications in CKD patients. Although administrating VEGF or novel drugs that activate VEGF pathway may improve the progression of CKD, careful monitoring will be required when CKD patients have complications of diabetes, atherosclerosis or sepsis.
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PMID:Role of vascular endothelial growth factor in kidney disease. 1948 13

The wet form of age related macular degeneration (AMD), known also as exudative or neovascular, is characterized by the formation of a pathological choroidal neovascular membrane (CNV) responsible for most cases of severe blindness. Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein acting as a growth factor selective for endothelial cells; it regulates angiogenesis and enhances vascular permeability and plays a leading role in this disorder. The consistent association between CNV and increased VEGF-A expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of neovascular AMD. The importance of VEGF for the development of AMD-related CNV has led to the development of a strategy able to block its pathologic effects. The rationale is that a blockade of VEGF actions could be effective in arresting choroidal angiogenesis and also reducing the vascular permeability, which is frequently the main cause of visual acuity deterioration. However, VEGF has also important functions in vascular physiology. The effects of anti-VEGF therapy may inhibit these functions. Herein we report the systemic adverse events secondary to intravitreal administration of these compounds i.e. the main cardiovascular effects (thrombosis, hemorrhage, hypertension, proteinuria), as well as the less frequent cerebrovascular accidents, myocardial infarction, transient ischemic attacks, deep vein thrombosis, pulmonary embolism and thrombophlebitis.
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PMID:Systemic adverse drug reactions secondary to anti-VEGF intravitreal injection in patients with neovascular age-related macular degeneration. 2147 Jan 8

Patients with end-stage renal disease (ESRD) are known to have an elevation of a variety of abnormal thrombotic and inflammatory markers associated with high cardiovascular mortality. Vascular endothelial growth factor (VEGF) is also dysregulated in ESRD but not much is known about the serum levels of VEGF in patients with ESRD. Published reports suggest that elevated levels of VEGF may be protective to the kidney during periods of acute injury and may maintain local glomerular function. Impaired production of VEGF may lead to proteinuria, hypertension, and thrombotic microangiopathy. However, its role in chronic kidney disease or ESRD remains undefined. In our study, we analyzed blood samples of 52 patients with ESRD on stable hemodialysis regimen and measured predialysis serum levels of VEGF and compared these with blood samples obtained from 50 healthy volunteers in order to study differences between baseline levels of VEGF and also attempted to determine its role in ESRD-related cardiovascular mortality.
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PMID:Assessment of levels of vascular endothelial growth factor in patients with ESRD and its possible role in cardiovascular morbidity and mortality. 2231 31


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