Skip to main content

Advertisement

Log in

Vascular endothelial growth factor and diabetic nephropathy

  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

The field of vascular endothelial growth factor (VEGF) has recently witnessed a surge of research into its role in diabetic kidney disease. Based on its credentials as a potent inducer of vasopermeability and angiogenesis, podocyte-derived VEGF is believed to participate in the glomerular capillary hyperpermeability of macromolecules that potentially underlies the pathogenesis of diabetic albuminuria. The evidence for VEGF’s role is relatively straightforward in animal models of diabetes, establishing that VEGF is upregulated in the diabetic kidney, that VEGF alone reproduces some aspects of diabetic glomerulopathy, and that antagonism of VEGF attenuates diabetic albuminuria and other associated features of the podocytopathy. However, the promise shown in the animal studies has not carried over as convincingly into the realm of human studies, as some investigators find a negative or no relationship between VEGF and diabetic nephropathy, whereas others find a positive correlation between the two. If VEGF does play a role in diabetic renal disease, its observed effects and known mechanisms seem to point squarely at the podocyte as a central target of the maladaptive VEGF overactivity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Ziyadeh FN, Wolf G: Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev 2008, 4:39–45.

    Article  PubMed  CAS  Google Scholar 

  2. Senger DR, Galli SJ, Dvorak AM, et al.: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983, 219:983–985.

    Article  PubMed  CAS  Google Scholar 

  3. Nakagawa T: Uncoupling of the VEGF-endothelial nitric oxide axis in diabetic nephropathy: an explanation for the paradoxical effects of VEGF in renal disease. Am J Physiol Renal Physiol 2007, 292:F1665–F1672.

    Article  PubMed  CAS  Google Scholar 

  4. Weis SM, Cheresh DA: Pathophysiological consequences of VEGF-induced vascular permeability. Nature 2005, 437:497–504.

    Article  PubMed  CAS  Google Scholar 

  5. Wang A, Ziyadeh FN, Lee EY, et al.: Interference with TGF-beta signaling by Smad3-knockout in mice limits diabetic glomerulosclerosis without affecting albuminuria. Am J Physiol Renal Physiol 2007, 293:F1657–F1665.

    Article  PubMed  CAS  Google Scholar 

  6. Ichinose K, Maeshima Y, Yamamoto Y, et al.: Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model. Diabetes 2005, 54:2891–2903.

    Article  PubMed  CAS  Google Scholar 

  7. Yamamoto Y, Maeshima Y, Kitayama H, et al.: Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy. Diabetes 2004, 53:1831–1840.

    Article  PubMed  CAS  Google Scholar 

  8. Cooper ME, 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, 48:2229–2239.

    Article  PubMed  CAS  Google Scholar 

  9. Singh AK, Gudehithlu KP, Pegoraro AA, et al.: Vascular factors altered in glucose-treated mesangial cells and diabetic glomeruli. Changes in vascular factors impair endothelial cell growth and matrix. Lab Invest 2004, 84:597–606.

    Article  PubMed  CAS  Google Scholar 

  10. Lee EY, Shim MS, Kim MJ, et al.: Angiotensin II receptor blocker attenuates overexpression of vascular endothelial growth factor in diabetic podocytes. Exp Mol Med 2004, 36:65–70.

    PubMed  CAS  Google Scholar 

  11. Sung SH, Ziyadeh FN, Wang A, et al.: Blockade of vascular endothelial growth factor signaling ameliorates diabetic albuminuria in mice. J Am Soc Nephrol 2006, 17:3093–3104.

    Article  PubMed  CAS  Google Scholar 

  12. Wang Z, Jiang T, Li J, et al.: Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes. Diabetes 2005, 54:2328–2335.

    Article  PubMed  CAS  Google Scholar 

  13. Tsuchida K, Makita Z, Yamagishi S, et al.: Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195. Diabetologia 1999, 42:579–588.

    Article  PubMed  CAS  Google Scholar 

  14. Cha DR, Kang YS, Han SY, et al.: Vascular endothelial growth factor is increased during early stage of diabetic nephropathy in type II diabetic rats. J Endocrinol 2004, 183:183–194.

    Article  PubMed  CAS  Google Scholar 

  15. Hoshi S, Shu Y, Yoshida F, et al.: Podocyte injury promotes progressive nephropathy in Zucker diabetic fatty rats. Lab Invest 2002, 82:25–35.

    PubMed  CAS  Google Scholar 

  16. Braun L, Kardon T, Reisz-Porszasz ZS, et al.: The regulation of the induction of vascular endothelial growth factor at the onset of diabetes in spontaneously diabetic rats. Life Sci 2001, 69:2533–2542.

    Article  PubMed  CAS  Google Scholar 

  17. Belteki G, Haigh J, Kabacs N, et al.: Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction. Nucleic Acids Res 2005, 33:e51.

    Article  PubMed  Google Scholar 

  18. Sison K, Fantus IG, Quaggin SE: Podocyte-specific increase in VEGF-A production leads to rapid alterations in glomerular permeability and features of diabetic nephropathy [abstract F-FC193]. Presented at the 38th Annual American Society of Nephrology Meeting. Philadelphia; November 10–13, 2005.

  19. Wilkinson L, Gilbert T, Kinna G, et al.: Crim1KST264/ KST264 mice implicate Crim1 in the regulation of vascular endothelial growth factor-A activity during glomerular vascular development. J Am Soc Nephrol 2007, 18:1697–1708.

    Article  PubMed  CAS  Google Scholar 

  20. Klanke B, Simon M, Rockl 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, 13:875–885.

    Article  PubMed  CAS  Google Scholar 

  21. De Vriese AS, Tilton RG, Elger M, et al.: Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J Am Soc Nephrol 2001, 12:993–1000.

    PubMed  Google Scholar 

  22. Flyvbjerg A, Dagnaes-Hansen F, De Vriese AS, et al.: Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody. Diabetes 2002, 51:3090–3094.

    Article  PubMed  CAS  Google Scholar 

  23. Shulman K, Rosen S, Tognazzi K, et al.: Expression of vascular permeability factor (VPF/VEGF) is altered in many glomerular diseases. J Am Soc Nephrol 1996, 7:661–666.

    PubMed  CAS  Google Scholar 

  24. Baelde HJ, Eikmans M, Lappin DW, et al.: Reduction of VEGF-A and CTGF expression in diabetic nephropathy is associated with podocyte loss. Kidney Int 2007, 71:637–645.

    Article  PubMed  CAS  Google Scholar 

  25. Bailey E, Bottomley MJ, 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, 52:735–738.

    Article  PubMed  CAS  Google Scholar 

  26. Bortoloso E, Del Prete D, Dalla Vestra M, 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.

    Article  PubMed  CAS  Google Scholar 

  27. Lindenmeyer MT, Kretzler M, Boucherot A, et al.: Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy. J Am Soc Nephrol 2007, 18:1765–1776.

    Article  PubMed  CAS  Google Scholar 

  28. Kanesaki Y, Suzuki D, Uehara G, et al.: Vascular endothelial growth factor gene expression is correlated with glomerular neovascularization in human diabetic nephropathy. Am J Kidney Dis 2005, 45:288–294.

    Article  PubMed  CAS  Google Scholar 

  29. Janickova Zdarska D, Zavadova E, Kvapil M: The effect of ramipril therapy on cytokines and parameters of incipient diabetic nephropathy in patients with type 1 diabetes mellitus. J Int Med Res 2007, 35:374–383.

    PubMed  CAS  Google Scholar 

  30. Hohenstein B, Hausknecht B, Boehmer K, et al.: Local VEGF activity but not VEGF expression is tightly regulated during diabetic nephropathy in man. Kidney Int 2006, 69:1654–1661.

    Article  PubMed  CAS  Google Scholar 

  31. Cipriani R, Sensi M, Gabriele A, et al.: The impairment of renal function is not associated to altered circulating vascular endothelial growth factor in patients with type 2 diabetes and hypertension. Diabetes Nutr Metab 2004, 17:90–94.

    PubMed  CAS  Google Scholar 

  32. Baba T, Osterby R, Neugebauer-Baba S, et al.: No nephropathy in type 2 diabetic patient with POEMS syndrome with an elevated plasma VEGF. Diabet Med 2004, 21:292–294.

    Article  PubMed  CAS  Google Scholar 

  33. Honkanen EO, Teppo AM, Gronhagen-Riska C: Decreased urinary excretion of vascular endothelial growth factor in idiopathic membranous glomerulonephritis. Kidney Int 2000, 57:2343–2349.

    Article  PubMed  CAS  Google Scholar 

  34. Lenz T, Haak T, Malek J, et al.: Vascular endothelial growth factor in diabetic nephropathy. Kidney Blood Press Res 2003, 26:338–343.

    Article  PubMed  CAS  Google Scholar 

  35. Shimada K, Baba T, Neugebauer S, et al.: Plasma vascular endothelial growth factor in Japanese type 2 diabetic patients with and without nephropathy. J Diabetes Complications 2002, 16:386–390.

    Article  PubMed  CAS  Google Scholar 

  36. Hovind P, Tarnow L, Oestergaard PB, Parving HH: Elevated vascular endothelial growth factor in type 1 diabetic patients with diabetic nephropathy. Kidney Int Suppl 2000, 75:S56–S61.

    Article  PubMed  CAS  Google Scholar 

  37. 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, 17:650–656.

    Article  PubMed  CAS  Google Scholar 

  38. Santilli F, Spagnoli A, Mohn A, et al.: Increased vascular endothelial growth factor serum concentrations may help to identify patients with onset of type 1 diabetes during childhood at risk for developing persistent microalbuminuria. J Clin Endocrinol Metab 2001, 86:3871–3876.

    Article  PubMed  CAS  Google Scholar 

  39. Kim NH, Kim KB, Kim DL, et al.: Plasma and urinary vascular endothelial growth factor and diabetic nephropathy in type 2 diabetes mellitus. Diabet Med 2004, 21:545–551.

    Article  PubMed  CAS  Google Scholar 

  40. Kim NH, Oh JH, Seo JA, et al.: Vascular endothelial growth factor (VEGF) and soluble VEGF receptor FLT-1 in diabetic nephropathy. Kidney Int 2005, 67:167–177.

    Article  PubMed  CAS  Google Scholar 

  41. Ray D, Mishra M, Ralph S, et al.: Association of the VEGF gene with proliferative diabetic retinopathy but not proteinuria in diabetes. Diabetes 2004, 53:861–864.

    Article  PubMed  CAS  Google Scholar 

  42. Baelde HJ, Eikmans M, Doran PP, et al.: Gene expression profiling in glomeruli from human kidneys with diabetic nephropathy. Am J Kidney Dis 2004, 43:636–650.

    Article  PubMed  CAS  Google Scholar 

  43. Buraczynska M, Ksiazek P, Baranowicz-Gaszczyk I, Jozwiak L: Association of the VEGF gene polymorphism with diabetic retinopathy in type 2 diabetes patients. Nephrol Dial Transplant 2007, 22:827–832.

    Article  PubMed  CAS  Google Scholar 

  44. Al-Kateb H, Mirea L, Xie X, et al.: Multiple variants in vascular endothelial growth factor (VEGFA) are risk factors for time to severe retinopathy in type 1 diabetes: the DCCT/EDIC genetics study. Diabetes 2007, 56:2161–2168.

    Article  PubMed  CAS  Google Scholar 

  45. Yang B, Cross DF, 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, 17:1–6.

    Article  PubMed  Google Scholar 

  46. McKnight AJ, Maxwell AP, Patterson CC, et al.: Association of VEGF-1499C→T polymorphism with diabetic nephropathy in type 1 diabetes mellitus. J Diabetes Complications 2007, 21:242–245.

    Article  PubMed  Google Scholar 

  47. Zeng L, Xu H, Chew TL, et al.: HMG CoA reductase inhibition modulates VEGF-induced endothelial cell hyper-permeability by preventing RhoA activation and myosin regulatory light chain phosphorylation. FASEB J 2005, 19:1845–1847.

    PubMed  CAS  Google Scholar 

  48. Eremina V, Baelde HJ, Quaggin SE: Role of the VEGF-A signaling pathway in the glomerulus: evidence for crosstalk between components of the glomerular filtration barrier. Nephron Physiol 2007, 106:p32–p37.

    Article  PubMed  CAS  Google Scholar 

  49. Chen S, Kasama Y, Lee JS, 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.

    Article  PubMed  CAS  Google Scholar 

  50. Ichinose K, Maeshima Y, Yamamoto Y, et al.: 2-(8-hydroxy-6-methoxy-1-oxo-1h-2-benzopyran-3-yl) propionic acid, an inhibitor of angiogenesis, ameliorates renal alterations in obese type 2 diabetic mice. Diabetes 2006, 55:1232–1242.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fuad N. Ziyadeh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, S., Ziyadeh, F.N. Vascular endothelial growth factor and diabetic nephropathy. Curr Diab Rep 8, 470–476 (2008). https://doi.org/10.1007/s11892-008-0081-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-008-0081-3

Keywords

Navigation