The role of vascular endothelial growth factor (VEGF) in renal pathophysiology
2004; Elsevier BV; Volume: 65; Issue: 6 Linguagem: Inglês
10.1111/j.1523-1755.2004.00621.x
ISSN1523-1755
AutoresBieke F. Schrijvers, Allan Flyvbjerg, An S. De Vriese,
Tópico(s)Lymphatic System and Diseases
ResumoThe 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. 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. Vascular endothelial growth factor (VEGF-A or VEGF), formerly called vasculotropin or vascular permeability factor (VPF), belongs to a family of multipotent cytokines, also including VEGF-B, -C, -D, -E, and placenta growth factor [1.Ferrara N. Gerber H.P. The role of vascular endothelial growth factor in angiogenesis.Acta Haematol. 2001; 106: 148-156Google Scholar]. Alternative exon splicing of a single VEGF gene results in at least six different isoforms. They are homodimeric glycoproteins of 121, 145, 165, 183, 189, and 206 amino acids (VEGF121-206) in humans and are one amino acid shorter in rodents [2.Neufeld G. Cohen T. Gengrinovitch S. Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors.FASEB J. 1999; 13: 9-22Google Scholar]. VEGF121, VEGF165, and VEGF189 are the most abundantly expressed isoforms, whereas VEGF145 and VEGF206 are comparatively rare [2.Neufeld G. Cohen T. Gengrinovitch S. Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors.FASEB J. 1999; 13: 9-22Google Scholar]. VEGF stimulates endothelial cell proliferation and differentiation, increases vascular permeability, mediates endothelium-dependent vasodilatation, and supports vascular survival by preventing endothelial apoptosis [1.Ferrara N. Gerber H.P. The role of vascular endothelial growth factor in angiogenesis.Acta Haematol. 2001; 106: 148-156Google Scholar, 2.Neufeld G. Cohen T. Gengrinovitch S. Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors.FASEB J. 1999; 13: 9-22Google Scholar]. In addition, VEGF induces plasminogen activator, plasminogen activator inhibitor-1 and interstitial collagenase, factors important in matrix remodeling. Furthermore, VEGF promotes monocyte chemotaxis and expression of adhesion molecules [1.Ferrara N. Gerber H.P. The role of vascular endothelial growth factor in angiogenesis.Acta Haematol. 2001; 106: 148-156Google Scholar, 2.Neufeld G. Cohen T. Gengrinovitch S. Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors.FASEB J. 1999; 13: 9-22Google Scholar]. VEGF165, VEGF189, and VEGF121 differ in affinity for heparin and heparan-sulfate proteoglycans (VEGF189 > VEGF165 > VEGF121) and in mitogenic effect (VEGF165 > VEGF121) [2.Neufeld G. Cohen T. Gengrinovitch S. Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors.FASEB J. 1999; 13: 9-22Google Scholar]. VEGF165, VEGF189, and VEGF206 are in most part sequestered in the extracellular matrix and at the cell surface, whereas VEGF121 and VEGF145 are freely released [2.Neufeld G. Cohen T. Gengrinovitch S. Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors.FASEB J. 1999; 13: 9-22Google Scholar]. The receptors for VEGF, previously described as fms-like tyrosine kinase (Flt-1) and fetal liver kinase 1 (Flk-1/KDR), now designated as VEGFR-1 and VEGFR-2, respectively, are high-affinity transmembrane tyrosine kinase receptors [2.Neufeld G. Cohen T. Gengrinovitch S. Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors.FASEB J. 1999; 13: 9-22Google Scholar]. Soluble VEGFR-1 (sVEGFR-1), a splice variant of VEGFR-1, regulates VEGF availability by binding VEGF in the circulation [3.Whittle C. Gillespie K. Harrison R. et al.Heterogeneous vascular endothelial growth factor (VEGF) isoform mRNA and receptor mRNA expression in human glomeruli, and the identification of VEGF148 mRNA, a novel truncated splice variant.Clin Sci. 1999; 97: 303-312Google Scholar, 4.Hornig C. Barleon B. Ahmad S. et al.Release and complex formation of soluble VEGFR-1 from endothelial cells and biologial fluids.Lab Invest. 2000; 80: 443-454Google Scholar]. Neuropilin-1 and Neuropilin-2 act as isoform specific co-receptors for VEGF [5.Nakamura F. Goshima Y. Structural and functional relation of neuropilins.Adv Exp Med Biol. 2002; 515: 55-69Google Scholar]. Hypoxia is the main stimulus for VEGF expression and/or production. Several growth factors and cytokines such as epidermal growth factor, transforming growth factor β (TGF-β), platelet-derived growth factor (PDGF), insulin-like growth factor I (IGF-I), angiotensin II, interleukin-1 (IL-1), and IL-6 also have the potential to up-regulate VEGF expression. VEGF may be induced by other factors as well [i.e., prostaglandins, mechanical stress, hyperglycemia, advanced glycation end products (AGEs), protein kinase C (PKC), and reactive oxygen species (ROS)]. VEGF up-regulates the expression of endothelial nitric oxide synthase (NOS3) in endothelial cells and increases the production of nitric oxide [6.Hood J.D. Meininger C.J. Ziche M. Granger H.J. VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells.Am J Physiol. 1998; 274: H1054-H1058Google Scholar]. Several lines of evidence have indicated that VEGF exerts its biologic effects through nitric oxide [7.Tilton R.G. Chang K.C. LeJeune W.S. et al.Role for nitric oxide in the hyperpermeability and hemodynamic changes induced by intravenous VEGF.Invest Ophthalmol Vis Sci. 1999; 40: 689-696Google Scholar]. Nitric oxide may down-regulate VEGF expression and thus function in a negative feedback regulator mechanism [8.Tsurumi Y. Murohara T. Krasinski K. et al.Reciprocal relation between VEGF and NO in the regulation of endothelial integrity.Nat Med. 1997; 3: 879-886Google Scholar]. Recently, 15 different sequence polymorphisms have been identified within the VEGF gene, including a C/T base change at position -460, a G/C change at +405 and a A/C change at -141 [9.Watson C.J. Webb N.J. Bottomley M.J. Brenchley P.E. Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: Correlation with variation in VEGF protein production.Cytokine. 2000; 12: 1232-1235Google Scholar]. The -460C/+405G and -460T/+405C haplotypes are the most frequently observed in the normal population [9.Watson C.J. Webb N.J. Bottomley M.J. Brenchley P.E. Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: Correlation with variation in VEGF protein production.Cytokine. 2000; 12: 1232-1235Google Scholar]. A correlation of the +405 genotype with production of VEGF has been demonstrated in vitro [9.Watson C.J. Webb N.J. Bottomley M.J. Brenchley P.E. Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: Correlation with variation in VEGF protein production.Cytokine. 2000; 12: 1232-1235Google Scholar] and in vivo [10.Awata T. Inoue K. Kurihara S. et al.A common polymorphism in the 5′-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes.Diabetes. 2002; 51: 1635-1639Google Scholar], with the highest VEGF production for the GG genotype, intermediate production for the GC genotype and lowest production for the CC genotype [9.Watson C.J. Webb N.J. Bottomley M.J. Brenchley P.E. Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: Correlation with variation in VEGF protein production.Cytokine. 2000; 12: 1232-1235Google Scholar]. Further, the combination of the +405G genotype with other polymorphisms resulted in higher VEGF promotor activity [11.Stevens A. Soden J. Brenchley P.E. et al.Haplotype analysis of the polymorphic human vascular endothelial growth factor gene promoter.Cancer Res. 2003; 63: 812-816Google Scholar]. A deletion/insertion (D/I) polymorphism at the -2549 position of the VEGF promotor region has been linked to increased transcriptional activity [12.Yang B. Cross D.F. Ollerenshaw M. et al.Polymorphisms of the vascular endothelial growth factor and susceptibility to diabetic microvascular complications in patients with type 1 diabetes mellitus.J Diabetes Complications. 2003; 17: 1-6Google Scholar]. Angiopoietins form another family of endothelial-specific growth factors consisting of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), which bind to tyrosine kinase receptors Tie1 and Tie2 [13.Satchell S.C. Mathieson P.W. Angiopoietins: Microvascular modulators with potential roles in glomerular pathophysiology.J Nephrol. 2003; 16: 168-178Google Scholar]. Angiopoietins and VEGF play co-ordinated and complementary roles in vascular homeostasis [13.Satchell S.C. Mathieson P.W. Angiopoietins: Microvascular modulators with potential roles in glomerular pathophysiology.J Nephrol. 2003; 16: 168-178Google Scholar]. Ang-2 stimulates new blood vessel formation in the presence of VEGF, but promotes endothelial apoptosis and vessel regression when VEGF levels are low [14.Lobov I.B. Brooks P.C. Lang R.A. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo.Proc Natl Acad Sci USA. 2002; 99: 11205-11210Google Scholar]. This section elaborates on the expression and the potential role of VEGF, angiopoietins, and their receptors in the normal adult kidney. A comprehensive discussion of the role of the VEGF system in renal development is beyond the scope and space limitations of this review and has been published elsewhere [15.Robert B. Abrahamson D.R. Control of glomerular capillary development by growth factor/receptor kinases.Pediatr Nephrol. 2001; 16: 294-301Google Scholar]. Cultured rat and human mesangial cells express both mRNA of VEGF121, VEGF165, and VEGF189, and VEGF protein [16.Cha D.R. Kim N.H. Yoon J.W. et al.Role of vascular endothelial growth factor in diabetic nephropathy.Kidney Int. 2000; 58: S104-S112Google Scholar, 17.Iijima K. Yoshikawa N. Connolly D.T. Nakamura H. Human mesangial cells and peripheral blood mononuclear cells produce vascular permeability factor.Kidney Int. 1993; 44: 959-966Google Scholar]. In rodent and human kidneys, VEGF mRNA and/or protein were detected predominantly in glomerular podocytes, distal tubules, and collecting ducts, and to a lesser extent in some proximal tubules [3.Whittle C. Gillespie K. Harrison R. et al.Heterogeneous vascular endothelial growth factor (VEGF) isoform mRNA and receptor mRNA expression in human glomeruli, and the identification of VEGF148 mRNA, a novel truncated splice variant.Clin Sci. 1999; 97: 303-312Google Scholar, 16.Cha D.R. Kim N.H. Yoon J.W. et al.Role of vascular endothelial growth factor in diabetic nephropathy.Kidney Int. 2000; 58: S104-S112Google Scholar, 18.Bailey E. Bottomley M.J. Westwell S. et al.Vascular endothelial growth factor mRNA expression in minimal change, membranous, and diabetic nephropathy demonstrated by non-isotopic in situ hybridisation.J Clin Pathol. 1999; 52: 735-738Google Scholar, 19.Cooper M.E. Vranes D. Youssef S. et al.Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes.Diabetes. 1999; 48: 2229-2239Google Scholar, 20.Gröne H.J. Simon M. Gröne E.F. Expression of vascular endothelial growth factor in renal vascular disease and renal allografts.J Pathol. 1995; 177: 259-267Google Scholar, 21.Kang D.H. Anderson S. Kim Y.G. et al.Impaired angiogenesis in the aging kidney: Vascular endothelial growth factor and thrombospondin-1 in renal disease.Am J Kidney Dis. 2001; 37: 601-611Google Scholar, 22.Kretzler M. Schröppel B. Merkle M. et al.Detection of multiple vascular endothelial growth factor splice isoforms in single glomerular podocytes.Kidney Int. 1998; 41: S159-S161Google Scholar, 23.Simon M. Gröne H.J. Johren O. et al.Expression of vascular endothelial growth factor and its receptors in human renal ontogenesis and in adult kidney.Am J Physiol. 1995; 268: F240-F250Google Scholar]. The expression of the different VEGF isoforms in normal human glomeruli was complex and variable with substantial inter- and intraindividual variation [3.Whittle C. Gillespie K. Harrison R. et al.Heterogeneous vascular endothelial growth factor (VEGF) isoform mRNA and receptor mRNA expression in human glomeruli, and the identification of VEGF148 mRNA, a novel truncated splice variant.Clin Sci. 1999; 97: 303-312Google Scholar]. Ang-1, but not Ang-2, was identified in adult human glomeruli, particularly in podocytes [24.Satchell S.C. Harper S.J. Tooke J.E. et al.Human podocytes express angiopoietin 1, a potential regulator of vascular endothelial growth factor.J Am Soc Nephrol. 2002; 13: 544-550Google Scholar]. VEGFR-1 and VEGFR-2 were detected in cultured rat and human mesangial cells [25.Amemiya T. Sasamura H. Mifune M. et al.Vascular endothelial growth factor activates MAP kinase and enhances collagen synthesis in human mesangial cells.Kidney Int. 1999; 56: 2055-2063Google Scholar, 26.Takahashi T. Shirasawa T. Miyake K. et al.Protein tyrosine kinases expressed in glomeruli and cultured glomerular cells: Flt-1 and VEGF expression in renal mesangial cells.Biochem Biophys Res Commun. 1995; 209: 218-226Google Scholar, 27.Thomas S. Vanuystel J. Gruden G. et al.Vascular endothelial growth factor receptors in human mesangium in vitro and in glomerular disease.J Am Soc Nephrol. 2000; 11: 1236-1243Google Scholar, 28.Trachtman H. Futterweit S. Franki N. Singhal P.C. Effect of vascular endothelial growth factor on nitric oxide production by cultured rat mesangial cells.Biochem Biophys Res Commun. 1998; 245: 443-446Google Scholar] and in cultured rat renal tubular epithelial cells [29.Kanellis J. Fraser S. Katerelos M. Power D.A. Vascular endothelial growth factor is a survival factor for renal tubular epithelial cells.Am J Physiol Renal Physiol. 2000; 278: F905-F915Google Scholar], but not in cultured primary human podocytes [30.Harper S.J. Xing C.Y. Whittle C. et al.Expression of neuropilin-1 by human glomerular epithelial cells in vitro and in vivo.Clin Sci. 2001; 101: 439-446Google Scholar]. In contrast, conditionally immortalized human podocytes expressed VEGFR-1, VEGFR-3 and Neuropilin-1 but not VEGFR-2 [31.Foster R.R. Hole R. Anderson K. et al.Functional evidence that vascular endothelial growth factor may act as an autocrine factor on human podocytes.Am J Physiol Renal Phsysiol. 2003; 284: F1263-F1273Google Scholar]. Cultured mouse glomerular endothelial cells and transformed tubular epithelial cells expressed Neuropilin-1 and Neuropilin-2 [32.Villegas G. Tufro A. Ontogeny of semaphorins 3A and 3F and their receptors neuropilins 1 and 2 in the kidney.Gene Expr Patterns. 2002; 2: 151-155Google Scholar]. Neuropilin-1 was also detected in cultured human mesangial cells [25.Amemiya T. Sasamura H. Mifune M. et al.Vascular endothelial growth factor activates MAP kinase and enhances collagen synthesis in human mesangial cells.Kidney Int. 1999; 56: 2055-2063Google Scholar, 27.Thomas S. Vanuystel J. Gruden G. et al.Vascular endothelial growth factor receptors in human mesangium in vitro and in glomerular disease.J Am Soc Nephrol. 2000; 11: 1236-1243Google Scholar] and in cultured primary human glomerular podocytes [30.Harper S.J. Xing C.Y. Whittle C. et al.Expression of neuropilin-1 by human glomerular epithelial cells in vitro and in vivo.Clin Sci. 2001; 101: 439-446Google Scholar]. The expression of VEGFR-1, VEGFR-2, sVEGFR-1, and Neuropilin-1 in isolated human glomeruli was also heterogenous [3.Whittle C. Gillespie K. Harrison R. et al.Heterogeneous vascular endothelial growth factor (VEGF) isoform mRNA and receptor mRNA expression in human glomeruli, and the identification of VEGF148 mRNA, a novel truncated splice variant.Clin Sci. 1999; 97: 303-312Google Scholar, 30.Harper S.J. Xing C.Y. Whittle C. et al.Expression of neuropilin-1 by human glomerular epithelial cells in vitro and in vivo.Clin Sci. 2001; 101: 439-446Google Scholar]. In human kidney, VEGFR-1 and VEGFR-2 were predominantly expressed on preglomerular, glomerular, and peritubular endothelial cells [20.Gröne H.J. Simon M. Gröne E.F. Expression of vascular endothelial growth factor in renal vascular disease and renal allografts.J Pathol. 1995; 177: 259-267Google Scholar, 23.Simon M. Gröne H.J. Johren O. et al.Expression of vascular endothelial growth factor and its receptors in human renal ontogenesis and in adult kidney.Am J Physiol. 1995; 268: F240-F250Google Scholar, 27.Thomas S. Vanuystel J. Gruden G. et al.Vascular endothelial growth factor receptors in human mesangium in vitro and in glomerular disease.J Am Soc Nephrol. 2000; 11: 1236-1243Google Scholar, 33.Simon M. Röckl W. Hornig C. et al.Receptors of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in fetal and adult human kidney: Localization and [125I] VEGF binding sites.J Am Soc Nephrol. 1998; 9: 1032-1044Google Scholar]. In rat kidney, VEGFR-2 expression was detected in glomerular and peritubular endothelial cells, in distal convoluted tubules and collecting ducts, and in cortical interstitial fibroblast and medullary interstitial cells, whereas VEGFR-1 was expressed more diffuse in proximal and distal tubules [19.Cooper M.E. Vranes D. Youssef S. et al.Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes.Diabetes. 1999; 48: 2229-2239Google Scholar, 29.Kanellis J. Fraser S. Katerelos M. Power D.A. Vascular endothelial growth factor is a survival factor for renal tubular epithelial cells.Am J Physiol Renal Physiol. 2000; 278: F905-F915Google Scholar]. In human kidney, Neuropilin-1 was detected in glomerular podocytes [30.Harper S.J. Xing C.Y. Whittle C. et al.Expression of neuropilin-1 by human glomerular epithelial cells in vitro and in vivo.Clin Sci. 2001; 101: 439-446Google Scholar]. Neuropilin-1 and Neuropilin-2 were localized in peritubular capillary endothelial cells in adult mouse and rat kidney [32.Villegas G. Tufro A. Ontogeny of semaphorins 3A and 3F and their receptors neuropilins 1 and 2 in the kidney.Gene Expr Patterns. 2002; 2: 151-155Google Scholar]. Tie2 was demonstrated in glomerular capillary endothelial cells of human and rat glomeruli and in cultured human microvascular endothelial cells [24.Satchell S.C. Harper S.J. Tooke J.E. et al.Human podocytes express angiopoietin 1, a potential regulator of vascular endothelial growth factor.J Am Soc Nephrol. 2002; 13: 544-550Google Scholar]. In summary, in vivo, capillary endothelial cells express VEGFR-1, VEGFR-2, and Tie2, glomerular podocytes express Neuropilin-1 and produce VEGF and Ang-1. Although the functions of constitutively expressed VEGF and VEGF receptors in the normal kidney are largely unknown, some hypotheses may be derived from the peculiar distribution of the molecule and its receptors in the kidney. VEGF is strongly expressed by visceral epithelial cells while its binding sites are localized on glomerular endothelial cells. If one assumes the existence of a paracrine loop in the glomerulus, VEGF must move in the opposite direction of the glomerular filtrate in order to bind to its receptors. The presence of such complex mechanism suggests that the strategic localization of podocytes is required for the correct sensing and interpretation of the stimulus for VEGF release. VEGF may be involved in the induction and maintenance of the fenestrae in glomerular capillary endothelial cells [37.Eremina V. Sood M. Haigh J. et al.Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases.J Clin Invest. 2003; 111: 707Google Scholar]. Given the role of VEGF in promoting microvascular permeability, it has been speculated that VEGF may regulate glomerular permeability, although it is generally acknowledged that the capillary fenestrations do not represent the ultimate barrier to filtration. Recently, in vitro evidence indicated that VEGF may act as an autocrine factor on calcium homeostasis and cell survival in human podocytes [31.Foster R.R. Hole R. Anderson K. et al.Functional evidence that vascular endothelial growth factor may act as an autocrine factor on human podocytes.Am J Physiol Renal Phsysiol. 2003; 284: F1263-F1273Google Scholar]. In contrast to the prominent expression of the VEGF system in the adult kidney, the administration or inhibition of VEGF in normal adult animals appears to have only minimal effects. In the isolated perfused rat kidney, administration of VEGF increased the renal blood flow but did not influence the glomerular filtration rate or the permselectivity of the glomerular barrier wall [34.Klanke B. Simon M. Röckl W. et al.Effects of vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) on haemodynamics and permselectivity of the isolated perfused rat kidney.Nephrol Dial Transplant. 1998; 13: 875-885Google Scholar]. In vivo infusions of VEGF into the renal artery of rats did not influence protein excretion rate [34.Klanke B. Simon M. Röckl W. et al.Effects of vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) on haemodynamics and permselectivity of the isolated perfused rat kidney.Nephrol Dial Transplant. 1998; 13: 875-885Google Scholar]. The administration of neutralizing monoclonal anti-VEGF-antibodies to normal rats had no effect on glomerular filtration rate or glomerular volume [35.De Vriese A.S. Tilton R.G. Elger M. et al.Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes.J Am Soc Nephrol. 2001; 12: 993-1000Google Scholar]. Injection of a VEGF165 aptamer, an oligonucleotide-based VEGF165 antagonist, in normal rats had no effect on kidney and glomerular morphology, did not induce proteinuria and did not affect glomerular cell proliferation and the number of endothelial fenestrations [36.Ostendorf T. Kunter U. Eitner F. et al.VEGF(165) mediates glomerular endothelial repair.J Clin Invest. 1999; 104: 913-923Google Scholar]. In contrast, podocyte-specific heterozygous and homozygous deletions of VEGF in mice resulted in proteinuria and endotheliosis by 2½ weeks of age, and in perinatal lethality, respectively, with loss of endothelial fenestrations or failure to form fenestrations [37.Eremina V. Sood M. Haigh J. et al.Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases.J Clin Invest. 2003; 111: 707Google Scholar]. Conversely, podocyte-specific overexpression of VEGF165 led to a collapsing glomerulopathy [37.Eremina V. Sood M. Haigh J. et al.Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases.J Clin Invest. 2003; 111: 707Google Scholar]. VEGF mRNA and protein expression were increased at the onset of diabetes in genetically diabetic BioBreeding rats [38.Braun L. Kardon T. Reisz-Porszasz Z.S. et al.The regulation of the induction of vascular endothelial growth factor at the onset of diabetes in spontaneously diabetic rats.Life Sci. 2001; 69: 2533-2542Google Scholar], in glomerular podocytes, distal tubules and collecting ducts after 3 weeks and 32 weeks of streptozotocin (STZ)-diabetes in rats [19.Cooper M.E. Vranes D. Youssef S. et al.Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes.Diabetes. 1999; 48: 2229-2239Google Scholar] and in renal tubular and vascular compartments in STZ-diabetic rats with superimposed hypertension [39.Cheng H.F. Wang C.J. Moeckel G.W. et al.Cyclooxygenase-2 inhibitor blocks expression of mediators of renal injury in a model of diabetes and hypertension.Kidney Int. 2002; 62: 929-939Google Scholar]. More specifically, the VEGF164 and VEGF188 isoforms increased after STZ-diabetes induction which was reversed by insulin treatment [40.Chou E. Suzuma I. Way K.J. et al.Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic states: A possible explanation for impaired collateral formation in cardiac tissue.Circulation. 2002; 105: 373-379Google Scholar]. Glomerular VEGFR-1 and VEGFR-2 mRNA expression were higher after 6 weeks of STZ-diabetes [40.Chou E. Suzuma I. Way K.J. et al.Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic states: A possible explanation for impaired collateral formation in cardiac tissue.Circulation. 2002; 105: 373-379Google Scholar]. Similarly, VEGFR-2 mRNA was increased in glomerular and peritubular endothelial cells and interstitial cells after 3 weeks of STZ-diabetes but not after 32 weeks [19.Cooper M.E. Vranes D. Youssef S. et al.Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes.Diabetes. 1999; 48: 2229-2239Google Scholar]. To assess the role of VEGF in the pathophysiology of early renal dysfunction in diabetes, type 1 diabetic rats were treated with monoclonal neutralizing anti-VEGF-antibodies for 6 weeks. Inhibition of VEGF abolished the diabetes-associated glomerular hyperfiltration, glomerular hypertrophy, and urinary albumin excretion (UAE) without an effect on metabolic control [35.De Vriese A.S. Tilton R.G. Elger M. et al.Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes.J Am Soc Nephrol. 2001; 12: 993-1000Google Scholar]. In addition, the diabetes-associated up-regulation of NOS3 expression was prevented, further supporting the evidence that nitric oxide acts as a downstream mediator of VEGF [35.De Vriese A.S. Tilton R.G. Elger M. et al.Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes.J Am Soc Nephrol. 2001; 12: 993-1000Google Scholar]. Both increased [abstract; Abdel Aziz MY, Nephrol Dial Transplant 12:1538a, 1997] [41.Chiarelli F. Spagnoli A. Basciani 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: 650-656Google Scholar, 42.McLaren M. Elhadd T.A. Greene S.A. Belch J.J. Elevated plasma vascular endothelial cell growth factor and thrombomodulin in juvenile diabetic patients.Clin Appl Thromb Hemost. 1999; 5: 21-24Google Scholar] and unaltered [43.Diamant M. Hanemaaijer R. Verheijen J.H. et al.Elevat
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