VEGF gene polymorphism association with diabetic neuropathy

Vascular factors beside metabolic problems are involved in both etiopathogenesis of diabetic neuropathy, and more remarkably, later in “repair” phase, that governs the net balance between neuro-regenerative/degenerative reactions. Regarding ischemic nature of diabetic neuropathy that highlights necessity of blood vessels re-establishment during tissue healing, VEGF (vascular endothelial growth factor) has been recently the subject of extensive investigations in diabetic neuropathy (DNU). This growth factor possesses angiogenic potentials in addition to the hemodynamic functions. The distribution of VEGF gene polymorphisms at positions −7*C/T, −1001*G/C, −1154*G/A and −2578*C/A were analysed by ARMS–PCR in 248 type 1 diabetic British-Caucasian subjects (81 DNU+, 167 DNU−). We have found that distribution of a VEGF gene polymorphism at promoter region (−7*C/T) was significantly different between diabetic subjects with vs. without neuropathy and the allele (C) conferred susceptibility to DNU (P = 0.02; OR = 1.78, 95% CI 1.0–3.1). The present study indicates that polymorphism of the VEGF gene at position −7*C/T might be implicated in the pathogenesis of diabetic neuropathy as it may harbour some functional/regulatory potential in VEGF gene expression. However, this requires further studies in order to better understand its phenotypic impact and to investigate the prognostic value of this polymorphism in diabetic neuropathy as a chronic complication of diabetes.

[1]  Napoleone Ferrara,et al.  Vascular endothelial growth factor: basic science and clinical progress. , 2004, Endocrine reviews.

[2]  J. Tarbell,et al.  Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Penn State Retina Research Group. , 1998, Diabetes.

[3]  S. Tesfaye,et al.  Vascular factors in diabetic neuropathy , 1994, Diabetologia.

[4]  V. Lassmann-Vague,et al.  Increased prevalence of neurologic complications among insulin dependent diabetic patients of Algerian origin. , 1988, Diabete & metabolisme.

[5]  M. Bottomley,et al.  Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. , 2000, Cytokine.

[6]  K. Ikeda,et al.  The relationship between accumulation of advanced glycation end products and expression of vascular endothelial growth factor in human diabetic retinas , 1997, Diabetologia.

[7]  J. Isner,et al.  Reversal of experimental diabetic neuropathy by VEGF gene transfer. , 2001, The Journal of clinical investigation.

[8]  Li Dong,et al.  Effect of high glucose concentration on VEGF and PEDF expression in cultured retinal Müller cells , 2009, Molecular Biology Reports.

[9]  M B Brown,et al.  A Practical Two-Step Quantitative Clinical and Electrophysiological Assessment for the Diagnosis and Staging of Diabetic Neuropathy , 1994, Diabetes Care.

[10]  E. Bauer,et al.  Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells , 1992, Journal of cellular physiology.

[11]  Clustering of Long-Term Complications in Families With Diabetes in the Diabetes Control and Complications Trial , 1997, Diabetes.

[12]  L. Aiello,et al.  Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. , 1999, Diabetes.

[13]  L. Aiello,et al.  Role of vascular endothelial growth factor in diabetic vascular complications. , 2000, Kidney international. Supplement.

[14]  A. Demaine,et al.  Susceptibility to diabetic neuropathy in patients with insulin dependent diabetes mellitus is associated with a polymorphism at the 5′ end of the aldose reductase gene , 1998, Journal of neurology, neurosurgery, and psychiatry.

[15]  Xiaomin Liu,et al.  The timing of re-institution of good blood glucose control affects apoptosis and expression of Bax and Bcl-2 in the retina of diabetic rats , 2009, Molecular Biology Reports.

[16]  J. Williamson,et al.  Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor. , 1997, The Journal of clinical investigation.

[17]  M. Khamaisi,et al.  The emerging role of VEGF in diabetic kidney disease. , 2003, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[18]  L. Aiello,et al.  Hypoxic regulation of vascular endothelial growth factor in retinal cells. , 1995, Archives of ophthalmology.

[19]  Lei Zhang,et al.  Gene Transfer of an Engineered Transcription Factor Promoting Expression of VEGF-A Protects Against Experimental Diabetic Neuropathy , 2006, Diabetes.

[20]  W. Renner,et al.  A Common 936 C/T Mutation in the Gene for Vascular Endothelial Growth Factor Is Associated with Vascular Endothelial Growth Factor Plasma Levels , 2000, Journal of Vascular Research.

[21]  P. Harden,et al.  Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. , 2002, Journal of the American Society of Nephrology : JASN.

[22]  R. Holman,et al.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. , 1998 .

[23]  R. Tilton Diabetic vascular dysfunction: Links to glucose‐induced reductive stress and VEGF , 2002, Microscopy research and technique.

[24]  Jianqiu Zheng,et al.  Protective effect of puerarin on diabetic retinopathy in rats , 2009, Molecular Biology Reports.

[25]  E. Feldman,et al.  The Aetiology of Diabetic Neuropathy: the Combined Roles of Metabolic and Vascular Defects , 1995, Diabetic medicine : a journal of the British Diabetic Association.

[26]  J. Alroy,et al.  Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy , 2000, Nature Medicine.

[27]  H. Dvorak,et al.  Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. , 1995, The American journal of pathology.

[28]  P. Raskin,et al.  Report of the expert committee on the diagnosis and classification of diabetes mellitus. , 1999, Diabetes care.

[29]  E. Feldman,et al.  The role of growth factors in diabetic peripheral neuropathy , 2004, Journal of the peripheral nervous system : JPNS.

[30]  H. Biri,et al.  No association between polymorphism in the vascular endothelial growth factor gene at position−460 and sporadic prostate cancer in the Turkish population , 2008, Molecular Biology Reports.

[31]  Kenneth J. Hillan,et al.  Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene , 1996, Nature.

[32]  B. Gallacher,et al.  Glucose-Induced Protein Kinase C Activation Regulates Vascular Permeability Factor mRNA Expression and Peptide Production by Human Vascular Smooth Muscle Cells In Vitro , 1997, Diabetes.

[33]  Gang Wu,et al.  Polymorphism of VEGF-2578C/A associated with the risk and aggressiveness of nasopharyngeal carcinoma in a Chinese population , 2009, Molecular Biology Reports.

[34]  M. Cooper,et al.  Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy , 2001, Diabetologia.

[35]  Uk-Prospective-Diabetes-Study-Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) , 1998, The Lancet.

[36]  K. Skorecki,et al.  Hypoxic induction of vascular endothelial growth factor is markedly decreased in diabetic individuals who do not develop retinopathy. , 2000, Diabetes care.

[37]  M. Bartoli,et al.  Vascular endothelial growth factor and diabetic retinopathy: role of oxidative stress. , 2005, Current drug targets.

[38]  E. Seaquist,et al.  Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. , 1989, The New England journal of medicine.

[39]  M. Bartoli,et al.  Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives , 2003, Diabetes/metabolism research and reviews.

[40]  E. Van Obberghen,et al.  Regulation of Vascular Endothelial Growth Factor Expression by Advanced Glycation End Products* , 2001, The Journal of Biological Chemistry.

[41]  L. Chouchane,et al.  Combined effects of the angiogenic genes polymorphisms on prostate cancer susceptibility and aggressiveness , 2007, Molecular Biology Reports.

[42]  L. Lanting,et al.  Effects of high glucose on vascular endothelial growth factor expression in vascular smooth muscle cells. , 1997, The American journal of physiology.

[43]  L. Aiello,et al.  Circulating plasma vascular endothelial growth factor and microvascular complications of Type 1 diabetes mellitus: the influence of ACE inhibition , 2001, Diabetic medicine : a journal of the British Diabetic Association.

[44]  K. Jin,et al.  Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[45]  J. Williamson,et al.  Vascular dysfunction induced by AGE is mediated by VEGF via mechanisms involving reactive oxygen species, guanylate cyclase, and protein kinase C. , 2001 .

[46]  S. Genuth,et al.  The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. , 1993, The New England journal of medicine.

[47]  C. Moriscot,et al.  Association of diabetic neuropathy with Na/K ATPase gene polymorphism , 1997, Diabetologia.