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.


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 AT1 receptor antagonist, valsartan, or the AT2 receptor antagonist, PD123319.


RESULTS
Diabetes was associated with increased gene and protein expression of VEGF, VEGF-R2, Ang-1, Ang-2 and Tie-2. AT1 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-Tie-2 axes being modulated in the kidney by haemodynamic factors in the diabetic context.
Rizkalla
Bishoy
B
Department of Diabetic Complications, Vascular Division, Wynn Domain, Baker Medical Research Institute, Melbourne, Victoria, Australia.
Forbes
Josephine M
JM
Cao
Zemin
Z
Boner
Geoffrey
G
Cooper
Mark E
ME
D042683:Angiopoietin-1 / Q000235:genetics; D042702:Angiopoietin-2 / Q000235:genetics; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D015870:Gene Expression / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000502:physiology*; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics; D012084:Renin-Angiotensin System / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D042461:Vascular Endothelial Growth Factor A; D014662:Vasoconstrictor Agents; C073402:PD 123319; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2