Temporal renal expression of angiogenic growth factors and their receptors in experimental diabetes: role of the renin-angiotensin system

Objective It has been postulated that vascular endothelial growth factor (VEGF) plays a role in the progression of renal injury. However, the role of other angiogenic factors and their receptors, such as the angiopoietins and Tie2, and in particular their relation to renoprotective therapies, such as agents that interrupt the renin-angiotensin system, have not been studied in the context of diabetes-related renal injury. Design and methods Renal expression of VEGF, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and their receptors, VEGF-R2 and Tie-2, were assessed using reverse transcription-polymerase chain reaction, immunohistochemistry and Western blotting, in control and streptozotocin diabetic rats, untreated or receiving the AT(1) receptor antagonist, valsartan, or the AT(2) receptor antagonist, PD123319. Results Diabetes was associated with increased gene and protein expression of VEGF, VEGF-R2, Ang-1, Ang-2 and Tie-2. AT(1) receptor antagonism attenuated gene expression of these cytokines and receptors, yet PD123319, which had no effect on blood pressure, reduced VEGF-R2 and Ang-1 gene expression and decreased VEGF, Ang-1 and Ang-2 protein levels. Conclusions In experimental diabetes, there is significant upregulation within the kidney of various angiogenic cytokines and their receptors. Furthermore, the effects of angiotensin II receptor blockade on these parameters is consistent with the VEGF-VEGF-R2 and angiopoietin-Tie2 axes being modulated in the kidney by haemodynamic factors in the diabetic context. (C) 2005 Lippincott Williams Wilkins.