Inhibition of Vascular Endothelial Growth Factor (VEGF) Does Not Affect Early Renal Changes in a Rat Model of Lean Type 2 Diabetes

B. F. Schrijvers; A. S. De Vriese; R. G. Tilton; J. Van De Voorde; L. Denner; N. H. Lameire; A. Flyvbjerg

doi:10.1055/s-2005-861027

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2005; 37(1): 21-25
DOI: 10.1055/s-2005-861027

Original Basic

Inhibition of Vascular Endothelial Growth Factor (VEGF) Does Not Affect Early Renal Changes in a Rat Model of Lean Type 2 Diabetes

B. F. Schrijvers^1, ² , A. S. De Vriese^2, ³ , R. G. Tilton⁴ , J. Van De Voorde⁵ , L. Denner⁴ , N. H. Lameire² , A. Flyvbjerg¹

¹Medical Research Laboratories, Institute of Experimental Clinical Research, Aarhus University Hospital, Aarhus, Denmark
²Renal Unit, Department of Internal Medicine, Gent University Hospital, Gent, Belgium
³Renal Unit, Department of Internal Medicine, AZ Sint-Jan AV, Brugge, Belgium
⁴Division of Endocrinology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA
⁵Department of Physiology and Physiopathology, Gent University, Gent, Belgium

Abstract

Type 2 diabetes is the most frequent cause of end-stage renal failure in many Western countries. Approximately 10 - 15 % of all type 2 diabetics are lean. Various growth factors and cytokines have been implicated in the pathophysiology of diabetic kidney disease, including vascular endothelial growth factor (VEGF). To elucidate a role for VEGF in the renal changes associated with type 2 diabetes, we examined the effect of a VEGF-antibody (ab) on early renal changes in the Goto-Kakizaki (GK) rat, a lean type 2 diabetes model. GK-rats were treated for 6 weeks with the VEGF-ab or with an isotype-matched irrelevant IgG. Wistar rats were used as non-diabetic controls. Placebo-treated GK-rats showed a pronounced increase in glomerular volume and urinary albumin excretion (UAE) and no change in the renal expression of endothelial nitric oxide synthase (eNOS) compared to placebo-treated non-diabetic controls. Kidney weight and creatinine clearance were no different between the groups. VEGF-ab treatment had no effect on glomerular volume, UAE, eNOS expression, body weight, blood glucose levels or food intake, but lowered serum insulin levels in non-diabetic and diabetic animals. We conclude that VEGF inhibition has minimal effects on early renal changes in GK-rats.

Key words

Endothelial nitric oxide synthase (eNOS) - Glomerular volume - Goto-Kakizaki (GK) rat - Kidney growth - VEGF-antibody (ab)

Full Text

References

1 Zimmet P. The burden of type 2 diabetes: are we doing enough?. Diabetes Metab. 2003; 29 6S9-6S18
2 Harvey J N. Trends in the prevalence of diabetic nephropathy in type 1 and type 2 diabetes. Curr Opin Nephrol Hypertens. 2003; 12 317-322
3 Flyvbjerg A. Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease. Diabetologia. 2000; 43 1205-1223
4 De Vriese A S, Tilton R G, Elger M, Stephan C C, Kriz W, Lameire N H. Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J Am Soc Nephrol. 2001; 12 993-1000
5 Flyvbjerg A, Dagnæs-Hansen F, De Vriese A S, Schrijvers B F, Tilton R G, Rasch R. 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
6 Boehm B O, Lang G, Feldmann B, Kurkhaus A, Rosinger S, Volpert O, Lang G K, Bouck N. Proliferative diabetic retinopathy is associated with a low level of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor. A pilot study. Horm Metab Res. 2003; 35 382-386
7 Schrijvers B F, De Vriese A S, Van de Voorde J, Rasch R, Lameire N H, Flyvbjerg A. Long-term renal changes in the Goto-Kakizaki rat, a model of lean type 2 diabetes. Nephrol Dial Transplant. 2004; 19 1-6
8 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-H1058
9 Tilton R G, Chang K C, LeJeune W S, Stephan C C, Brock T A, Williamson J R. Role for nitric oxide in the hyperpermeability and hemodynamic changes induced by intravenous VEGF. Invest Ophthalmol Vis Sci. 1999; 40 689-696
10 Tilton R G, Kawamura T, Chang K C, Ido Y, Bjercke R J, Stephan C C, Brock T A, Williamson J R. Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor. J Clin Invest. 1997; 99 2192-2202
11 Christensen C, Ørskov H. Rapid screening PEG radioimmunoassay for quantification of pathological microalbuminuria. Diabetic Nephrology. 1984; 3 92-94
12 Gundersen H J, Bagger P, Bendtsen T F, Evans S M, Korbo L, Marcussen N, Moller A, Nielsen K, Nyengaard J R, Pakkenberg B. The new stereological tools: disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. APMIS. 1988; 96 857-881
13 Weibel E R. Stereologic methods. Practical methods for biological morphometry. London; Academic Press 1979: 51-57
14 Cha D R, Kim N H, Yoon J W, Jo S K, Cho W Y, Kim H K, Won N H. Role of vascular endothelial growth factor in diabetic nephropathy. Kidney Int Suppl. 2000; 77 S104-S112
15 Miele C, Rochford J J, Filippa N, Giorgetti-Peraldi S, van Obberghen E. Insulin and insulin-like growth factor-I induce vascular endothelial growth factor mRNA expression via different signaling pathways. J Biol Chem. 2000; 275 21 695-21 702
16 Stallmeyer B, Pfeilschifter J, Frank S. Systemically and topically supplemented leptin fails to reconstitute a normal angiogenic response during skin repair in diabetic ob/ob mice. Diabetologia. 2001; 44 471-479
17 Cooper M E, Vranes D, Youssef S, Stacker S A, Cox A J, Rizkalla B, Casley D J, Bach L A, Kelly D J, Gilbert R E. Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes. 1999; 48 2229-2239
18 Chou E, Suzuma I, Way K J, Opland D, Clermont A C, Naruse K, Suzuma K, Bowling N L, Vlahos C J, Aiello L P, King G L. 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; 105 373-379
19 Schrijvers B F, Rasch R, Tilton R G, Flyvbjerg A. High protein-induced glomerular hypertrophy is vascular endothelial growth factor-dependent. Kidney Int. 2002; 61 1600-1604
20 Flyvbjerg A, Schrijvers B F, De Vriese A S, Tilton R G, Rasch R. Compensatory glomerular growth after unilateral nephrectomy is VEGF dependent. Am J Physiol Endocrinol Metab. 2002; 283 E362-E366
21 Goto Y, Kakizaki M, Masaki N. Spontaneous diabetes produced by selective breeding of normal wistar rats. Proc Japan Acad. 1975; 51 80-85
22 Ling Z C, Efendic S, Wibom R, Abdel-Halim S M, Östenson C G, Landau B R, Khan A. Glucose metabolism in Goto-Kakizaki rat islets. Endocrinology. 1998; 139 2670-2675
23 Wolf G, Chen S, Han D C, Ziyadeh F N. Leptin and renal disease. Am J Kidney Dis. 2002; 39 1-11
24 Christofori G, Naik P, Hanahan D. Vascular endothelial growth factor and its receptors, flt-1 and flk-1, are expressed in normal pancreatic islets and throughout islet cell tumorigenesis. Mol Endocrinol. 1995; 9 1760-1770
25 Öberg-Welsh C, Sandler S, Andersson A, Welsh M. Effects of vascular endothelial growth factor on pancreatic duct cell replication and the insulin production of fetal islet-like cell clusters in vitro. Mol Cell Endocrinol. 1997; 126 125-132
26 Lammert E, Gu G, McLaughlin M, Brown D, Brekken R, Murtaugh L C, Gerber H P, Ferrara N, Melton D A. Role of VEGF-A in vascularization of pancreatic islets. Curr Biol. 2003; 13 1070-1074

Bieke Schrijvers, M. D.

Renal Unit, 0K12A, Gent University Hospital

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Phone: +32 (9) 2403365

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Email: Bieke.Schrijvers@UGent.be