Background/Aims: Vascular endothelial growth factor is a major regulator of angiogenesis and vascular permeability [Carmeliet et al.: Nature 1996;380:435–439]. The podocyte, the outermost layer of the glomerular filtration barrier, produces large amounts of VEGF-A. The observation that levels of VEGF-A are altered in glomerular diseases, the identification of a link between pre-eclampsia and elevated levels of a circulating soluble VEGF receptor, and the entry of anti-VEGF therapies into the clinical arena have generated intense interest in the functional role of VEGF-A in the glomerulus. Methods: A variety of studies have been performed to address the role of VEGF-A signaling in the glomerulus. These include descriptions of expression patterns in human renal biopsies, cell culture studies to dissect paracrine versus autocrine signaling roles, and manipulation of VEGF-A expression in animal models using pharmacologic, biologic or genetic approaches. Results: Exquisite dosage sensitivity to VEGF-A exists in the developing glomerulus as small reductions in the expression of VEGF-A lead to profound changes in glomerular structure and function in mice. The use of VEGF inhibitors is associated with damage to the glomerular endothelium in animal models and proteinuria in patients, suggesting that local VEGF-A production is also required for maintenance of this specialized vascular bed. Conclusions: Tight regulation of VEGF-A signaling is required for development and maintenance of the glomerular filtration barrier (GFB) and emphasizes the role of podocyte-endothelial crosstalk in the glomerulus. The relative contributions of various VEGF-A isoforms, the role of autocrine signaling in vivo and identification of factors and mechanisms that regulate constitutive expression, storage and delivery of VEGF-A in the glomerulus are still under investigation.

Keywords:
VEGF-A, Podocyte, Endothelium, Glomerulus, Glomerular filtration barrier
1.
Carmeliet P, et al: Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996;380:435–439.
2.
Benjamin LE, Hemo I, Keshet E: A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF- B and VEGF. Development 1998;125:1591–1598.
3.
Ferrara N, Gerber HP: The role of vascular endothelial growth factor in angiogenesis. Acta Haematol 2001;106:148–156.
4.
Gerber HP, et al: VEGF is required for growth and survival in neonatal mice. Development 1999;126:1149–1159.
5.
Abrahamson DR: Glomerulogenesis in the developing kidney. Semin Nephrol 1991;11:375–389.
6.
Hyink DP, Abrahamson DR: Origin of the glomerular vasculature in the developing kidney. Semin Nephrol 1995;15:300–314.
7.
Ostendorf T, et al: VEGF(165) mediates glomerular endothelial repair. J Clin Invest 1999;104:913–923.
8.
Pierce EA, et al: Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci USA 1995;92:905–909.
9.
Eremina V, et al: Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003;111:707–716.
10.
Leveen P, et al: Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev 1994;8:1875–1887.
11.
Lindahl P, et al: Paracrine PDGF-B/PDGF-Rbeta signaling controls mesangial cell development in kidney glomeruli. Development 1998;125:3313–3322.
12.
Eremina V, et al: VEGF-A signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. JASN 2006;17:724–735.
13.
Mancuso MR, et al: Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 2006;116:2610–2621.
14.
Bates DO, et al: VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Res 2002;62:4123–4131.
15.
Bates DO, Harper SJ: Therapeutic potential of inhibitory VEGF splice variants. Future Oncol 2005;1:467–473.
16.
Mattot V, et al: Loss of the VEGF(164) and VEGF(188) isoforms impairs postnatal glomerular angiogenesis and renal arteriogenesis in mice. J Am Soc Nephrol 2002;13:1548–1560.
17.
Bortoloso E, et al: Quantitative and qualitative changes in vascular endothelial growth factor gene expression in glomeruli of patients with type 2 diabetes. Eur J Endocrinol 2004;150:799–807.
18.
Freeburg PB, et al: Podocyte expression of hypoxia-inducible factor (HIF)-1 and HIF-2 during glomerular development. J Am Soc Nephrol 2003;14:927–938.
19.
Datta K, et al: Regulation of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF-A) expression in podocytes. Kidney Int 2004;66:1471–1478.
20.
Gao X, et al: Angioblast-mesenchyme induction of early kidney development is mediated by Wt1 and Vegfa. Development 2005;132:5437–5449.
21.
Kang YS, et al: Angiotensin II stimulates the synthesis of vascular endothelial growth factor through the p38 mitogen activated protein kinase pathway in cultured mouse podocytes. J Mol Endocrinol 2006;36:377–388.
22.
Iglesias-de la Cruz MC, et al: Effects of high glucose and TGF-beta1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes. Kidney Int 2002;62:901–913.
23.
Hovind P, et al: Elevated vascular endothelial growth factor in type 1 diabetic patients with diabetic nephropathy. Kidney Int 2000;75(suppl):S56–S61.
24.
Chiarelli F, et al: Vascular endothelial growth factor (VEGF) in children, adolescents and young adults with type 1 diabetes mellitus: relation to glycaemic control and microvascular complications. Diabet Med 2000;17:650–656.
25.
McLaren M, et al: Elevated plasma vascular endothelial cell growth factor and thrombomodulin in juvenile diabetic patients. Clin Appl Thromb Hemost 1999;5:21–24.
26.
Foster RR, et al: Functional evidence that vascular endothelial growth factor may act as an autocrine factor on human podocytes. Am J Physiol 2003;284:F1263–F1273.
27.
Guan F, et al: Autocrine VEGF-A system in podocytes regulates podocin and its interaction with CD2AP. Am J Physiol 2006;291:F422–F428.
28.
Chen S, et al: Podocyte-derived vascular endothelial growth factor mediates the stimulation of alpha3(IV) collagen production by transforming growth factor-beta1 in mouse podocytes. Diabetes 2004;53:2939–2949.
29.
Foster RR, et al: Vascular endothelial growth factor and nephrin interact and reduce apoptosis in human podocytes. Am J Physiol 2005;288:F48–F57.
30.
Foster RR, et al: VEGF-C promotes survival in podocytes. Am J Physiol 2006;291:F196–F207.
31.
Partanen TA, et al: VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3, in fenestrated blood vessels in human tissues. FASEB J 2000;14:2087–2096.
32.
Maynard SE, et al: Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003;111:649–658.
33.
Levine RJ, et al: Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350:672–683.
34.
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 2003;278:12605–12608.
35.
Baelde HJ, et al: Reduction of VEGF-A and CTGF expression in diabetic nephropathy is associated with podocyte loss. Kidney Int 2007.
© 2007 S. Karger AG, Basel
2007
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