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      Vascular Endothelial Growth Factor Protein Expression in a Renal Ablation Rabbit Model under Prolonged Warm and Cold Ischemia

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          Abstract

          Background/Aims: To establish a potential correlation between renal and systemic production of vascular endothelial growth factor (VEGF) protein after prolonged ischemia in a renal ablation model under normothermic and hypothermic conditions. Methods: 38 uninephrectomized New Zealand rabbits were divided into 5 groups. The rabbits of each group underwent partial nephrectomy under 90 and 60 min of warm and 90 and 120 min of cold ischemia, except for the sham group (S), which served as control. Serum creatinine (SCr) and blood-urea-nitrogen (BUN) levels were assessed. On the 15th postoperative day (POD), the animals were euthanized and the remaining kidneys were evaluated. VEGF immunohistochemistry and serum Western blot analysis were performed. Results: In comparison to the control group, groups 60W, 90C and 120C showed 1.6-, 1.14- and 1.75-fold decreases, respectively, while the production of VEGF was significantly declined by 7.4-fold in group 90W (p < 0.05). Immunohistochemistry revealed prominent VEGF staining in the above-mentioned three groups, while in group 90W staining was negative. Serum biochemistry and microscopic evaluation verified the same differentiation. Conclusion: Renal and serum VEGF seem to have an analogous expression under conditions of prolonged ischemia. VEGF is overexpressed in hypothermic conditions compared to warm ischemia exceeding 60 min. Hypothermia can be more advantageous in a procedure applying prolonged ischemia.

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          Most cited references16

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          The role of vascular endothelial growth factor (VEGF) in renal pathophysiology.

          Vascular endothelial growth factor (VEGF) is an endothelial-specific growth factor that promotes endothelial cell proliferation, differentiation and survival, mediates endothelium-dependent vasodilatation, induces microvascular hyperpermeability and participates in interstitial matrix remodeling. In the kidney, VEGF expression is most prominent in glomerular podocytes and in tubular epithelial cells, while VEGF receptors are mainly found on preglomerular, glomerular, and peritubular endothelial cells. The role of VEGF in normal renal physiology is essentially unknown. The absence of prominent effects of VEGF blockade in normal experimental animals suggests a limited function during homeostasis, although a role in the formation and maintenance of glomerular capillary endothelial fenestrations has been suggested. VEGF and its receptors are up-regulated in experimental animals and humans with type 1 and type 2 diabetes. Inhibition of VEGF has beneficial effects on diabetes-induced functional and structural alterations, suggesting a deleterious role for VEGF in the pathophysiology of diabetic nephropathy. VEGF is required for glomerular and tubular hypertrophy and proliferation in response to nephron reduction, and loss of VEGF is associated with the development of glomerulosclerosis and tubulointerstitial fibrosis in the remnant kidney. No firm conclusions on the role of VEGF in minimal change or membranous glomerulonephritis can be drawn. VEGF may be an essential mediator of glomerular recovery in proliferative glomerulonephritis. Glomerular and tubulointerstitial repair in thrombotic microangiopathy and cyclosporin nephrotoxicity may also be VEGF-dependent. In conclusion, VEGF is required for growth and proliferation of glomerular and peritubular endothelial cells. While deleterious in some, it may contribute to recovery in other forms of renal diseases.
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            Vascular endothelial growth factor accelerates renal recovery in experimental thrombotic microangiopathy.

            Renal microvascular injury characterizes thrombotic microangiopathy (TMA). The possibility that angiogenic growth factors may accelerate recovery in TMA has not been studied. TMA was induced in rats by the selective right renal artery perfusion of antiglomerular endothelial cell IgG (30 mg/kg). Twenty-four hours later, rats received vascular endothelial growth factor (VEGF121, 100 microg/kg/day) or vehicle (control) daily until day 14. To evaluate renal function, the unperfused left kidney was removed at day 14, and rats were sacrificed at day 17. The induction of TMA was associated with loss of glomerular and peritubular capillary endothelial cells and decreased arteriolar density at day 1. Some spontaneous capillary recovery was present by day 17; however, repair was incomplete, and severe tubulointerstitial damage occurred. The lack of complete microvascular recovery was associated with reduced VEGF immunostaining in the outer medulla. VEGF-treated rats had more glomeruli with intact endothelium, less glomerular ischemia (collapsed glomeruli), and greater peritubular capillary density with less peritubular capillary loss. This was associated with less tubulointerstitial fibrosis, less cortical atrophy, and improved renal function. VEGF accelerates renal recovery in this experimental model of TMA. These studies suggest that angiogenic growth factors may provide a new therapeutic strategy for diseases associated with endothelial cell injury.
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              Major abdominal surgery increases plasma levels of vascular endothelial growth factor: open more so than minimally invasive methods.

              Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis that is necessary for wound healing and also promotes tumor growth. It is anticipated that plasma levels would increase after major surgery and that such elevations may facilitate tumor growth. This study's purpose was to determine plasma VEGF levels before and early after major open and minimally invasive abdominal surgery. Colorectal resection for cancer (n = 139) or benign pathology (n = 48) and gastric bypass for morbid obesity (n = 40) were assessed. Similar numbers of open and laparoscopic patients were studied for each indication. Plasma samples were obtained preoperatively and on postoperative days (POD) 1 and 3. VEGF levels were determined via ELISA. The following statistical methods were used: Fisher exact test, unmatched Student t test, Wilcoxon's matched pairs test, and the Mann Whitney U Test with P < 0.05 considered significant. The mean preoperative VEGF level of the cancer patients was significantly higher than baseline level of benign colon patients. Regardless of indication or surgical method, on POD3, significantly elevated mean VEGF levels were noted for each subgroup. In addition, on POD1, open surgery patients for all 3 indications had significantly elevated VEGF levels; no POD1 differences were noted for the closed surgery patients. At each postoperative time point for each procedure and indication, the open group's VEGF levels were significantly higher than that of the matching laparoscopic group. VEGF elevations correlated with incision length for each indication. As a group colon cancer patients prior to surgery have significantly higher mean VEGF levels than patients without tumors. Also, both open and closed colorectal resection and gastric bypass are associated with significantly elevated plasma VEGF levels early after surgery. This elevation is significantly greater and occurs earlier in open surgery patients. The duration and clinical importance of this finding is uncertain but merits further study.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2008
                April 2008
                20 December 2007
                : 28
                : 3
                : 438-445
                Affiliations
                aDepartment of Urology, Athens University Medical School, LAIKO Hospital, Departments of bHistology and Embryology, and cPathology, Athens University Medical School, and dDivision of Biotechnology, Biomedical Research Foundation of the Academy of Athens, Athens, and eDepartment of Urology, Patras University Medical School, Patras, Greece
                Article
                112809 Am J Nephrol 2008;28:438–445
                10.1159/000112809
                18097136
                d04a99c0-1fd5-4c00-947f-ee427b71cb04
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 24 August 2007
                : 16 November 2007
                Page count
                Figures: 4, Tables: 1, References: 25, Pages: 8
                Categories
                Original Report: Laboratory Investigation

                Cardiovascular Medicine,Nephrology
                Vascular endothelial growth factor,Acute renal failure,Ischemia-reperfusion,Partial nephrectomy,Renal ablation

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