Sugimoto, H. et al. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J. Biol. Chem. 278, 12605-12608

Harvard University, Cambridge, Massachusetts, United States
Journal of Biological Chemistry (Impact Factor: 4.6). 05/2003; 278(15):12605-8. DOI: 10.1074/jbc.C300012200
Source: PubMed

ABSTRACT There are about 2.5 million glomeruli in the kidneys each consisting of a barrel of glomerular basement membrane surrounded by glomerular endothelial cells on the inside and glomerular epithelial cells with established foot processes (podocytes) on the outside. Defects in this filtration apparatus lead to glomerular vascular leak or proteinuria. The role of vascular endothelial growth factor (VEGF) in the regulation of glomerular vascular permeability is still unclear. Recent studies indicate that patients receiving anti-VEGF antibody therapy may have an increased incidence of proteinuria. In a different setting, pregnancies complicated by preeclampsia are associated with elevated soluble VEGF receptor 1 protein (sFlt-1), endothelial cell dysfunction and proteinuria. These studies suggest that neutralization of physiologic levels of VEGF, a key endothelial survival factor, may lead to proteinuria. In the present study, we evaluated the potential of anti-VEGF neutralizing antibodies and sFlt-1 in the induction of proteinuria. Our studies demonstrate that anti-VEGF antibodies and sFlt-1 cause rapid glomerular endothelial cell detachment and hypertrophy, in association with down-regulation of nephrin, a key epithelial protein in the glomerular filtration apparatus. These studies suggest that down-regulation or neutralization of circulating VEGF may play an important role in the induction of proteinuria in various kidney diseases, some forms of cancer therapy and also in women with preeclampsia.

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    • "In pre - eclampsia , sFlt - 1 is elevated and has since been considered a marker for pre - eclampsia ( Vuorela et al . , 2000 ; Buhimschi et al . , 2005 ) . In Wt mice , neutralization of VEGF - induced proteinuria ( Sugimoto et al . , 2003 ) and sFlt - 1 gene transfer provoked pre - eclampsia - like signs ( Maynard et al . , 2003 ; Lu et al . , 2007 ) . Cudmore et al . ( 2007 ) showed that , in vitro , the overexpression of HO - 1 in endothelial cells by using a retrovirus - inhibited sFlt - 1 release , whereas HO - 1 inhibition potentiated sFlt - 1 production from endoth"
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    ABSTRACT: The onset of pregnancy implies the appearance of a new organ, the placenta. One main function of the placenta is to supply oxygen to the fetus via hemoproteins. In this review, we highlight the importance of the enzyme heme oxygenase-1 (HO-1) for pregnancy to be established and maintained. HO-1 expression is pivotal to promote placental function and fetal development, thus determining the success of pregnancy. The deletion of the gene Hmox1 in mice leads to inadequate remodeling of spiral arteries and suboptimal placentation followed by intrauterine growth restriction (IUGR) and fetal lethality. A partial Hmox1 deletion leads to IUGR as well, with heterozygote and wild-type fetuses being born, but Hmox1-/- significantly below the expected Mendelian rate. This strong phenotype is associated with diminished number of pregnancy-protective uterine natural killer (uNK) cells. Pregnant heterozygote females develop gestational hypertension. The protective HO-1 effects on placentation and fetal growth can be mimicked by the exogenous administration of carbon monoxide (CO), a product of heme catalyzed by HO-1. CO application promotes the in situ proliferation of uNK cells, restores placentation and fetal growth, while normalizing blood pressure. Similarly, HO-1 inhibition provokes hypertension in pregnant rats. The HO-1/CO axis plays a pivotal role in sustaining pregnancy and aids in the understanding of the biology of pregnancy and reveals a promising therapeutic application in the treatment of pregnancy complications.
    Frontiers in Pharmacology 12/2014; 5. DOI:10.3389/fphar.2014.00291 · 3.80 Impact Factor
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    • "In addition, the crucial role of VEGF in microvascular complications of diabetes has been recently examined [Long et al. 2010]. Pharmacological and genetic disruptions of VEGF have been shown to result in significant proteinuria and glomerular endotheliosis [Eremina et al. 2003; Sugimoto et al. 2003]. VEGF is known to have a central role in angiogenesis, vascular homeostasis, and the maintenance of capillary integrity, particularly in the kidney glomerulus [Long et al. 2010]. "
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    ABSTRACT: This study was designed to investigate the protective effect of tetramethylpyrazine isolated from Ligusticum chuanxiong, a traditional Chinese medicine, on diabetic nephropathy in a rat model, and to explore the possible mechanism involved in a protective function. Diabetes was induced in male Sprague-Dawley rats by a single intraperitoneal injection of 70mg/kg of streptozotocin. One week later, 200mg/kg/day of tetramethylpyrazine was administered intragastric gavage daily for 8 weeks. Renal functions and expression of vascular endothelial growth factor were examined at 4 and 8 weeks after tetramethylpyrazine administration. Blood glucose and renal function were significantly improved in the tetramethylpyrazine-treated group compared to the untreated diabetic rats. Diabetic nephropathy resulted in an increase in the expression of vascular endothelial growth factor, while tetramethylpyrazine administration greatly decreased the expression. Our results suggest that administration of tetramethylpyrazine may reduce kidney damage caused by diabetes. This protective effect may be mediated, in part, by downregulated expression of vascular endothelial growth factor in the kidney.
    Phytomedicine: international journal of phytotherapy and phytopharmacology 06/2011; 18(13):1148-52. DOI:10.1016/j.phymed.2011.05.003 · 2.88 Impact Factor
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    • "Although this proteinuria was largely asymptomatic and low-grade, high-grade proteinuria and acute kidney injury have been described in some cases [6] [18]. There is a profound body of evidence that VEGF is important in maintaining glomerular endothelial cell health and healing [19] and that its absence induces proteinuria, release of procoagulant proteins, and glomerular endotheliosis [16] [20]. All these studies indicate that neutralization of circulating VEGF (either by sFlt-1 or antiangiogenetic drugs) may play an important role in the induction of proteinuria in cancer therapy and in women with preeclampsia. "
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    ABSTRACT: Glomerular VEGF expression is critical for the maintenance and function of an intact filtration barrier. Alterations in glomerular VEGF bioavailability result in endothelial as well as in podocyte damage. Renal involvement in preeclampsia includes proteinuria, podocyturia, elevated blood pressure, edema, glomerular capillary endotheliosis, and thrombotic microangiopathy. At least the renal signs, symptoms, and other evidence can sufficiently be explained by reduced VEGF levels. The aim of this paper was to summarize our pathophysiological understanding of the renal involvement of preeclampsia and point out similarities to the renal side effects of VEGF-ablation therapy.
    Journal of pregnancy 01/2011; 2011:176973. DOI:10.1155/2011/176973
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