Systemic and local effects of angiotensin II blockade in experimental diabetic nephropathy.
BACKGROUND
Our objective was to evaluate the effect of blocking the renin-angiotensin system (RAS) on the expression of transforming growth factor-beta 1 (TGF-beta1), platelet derived growth factor-B (PDGF-B), tumour necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor (VEGF) in diabetic kidney glomeruli.


METHODS
1) Uninephrectomised streptozotocin induced diabetic rats were treated during eight months with vehicle (CD) or irbesartan (ID). Uninephrectomised non-diabetic rats were used as control group (ND). Protein urinary excretion and morphological renal damage were analysed. Glomerular expression of TGF-beta1, PDGF-B, VEGF and TNF-alpha were evaluated by Western blot and Immunohistochemistry. 2) Isolated glomeruli of diabetic rats were incubated 24-hours in the presence of different doses of irbesartan. Glomerular expression of TGF-beta1, PDGF-B, TNF-alpha and VEGF were determined by Western blot.


RESULTS
ND and ID presented lower renal injury and proteinuria than CD (p<0.05). Glomerular expression of TGF-beta1, PDGF-B, TNF-alpha and VEGF were similar in ND and ID, but lower than in CD (p<0.05). In addition, in isolated diabetic rat glomeruli, irbesartan reduced the content of all these factors.


CONCLUSIONS
Systemic and local administration of irbesartan lowers glomerular expression of TGF-beta1, PDGF-B, VEGF and TNF-alpha. These data suggest that part of the effect of lowering the expression of these growth factors and cytokines is due to a direct blockade of glomerular RAS.
Vieitez
Paula
P
Endocrinology Department, Ramon y Cajal Hospital, Madrid, Spain.
Gómez
Oscar
O
Uceda
Esther R
ER
Vera
María Eugenia
ME
Molina-Holgado
Eduardo
E
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D018450:Disease Progression; D007150:Immunohistochemistry; D000077405:Irbesartan; D007678:Kidney Glomerulus / Q000378:metabolism / Q000502:physiology; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D010982:Platelet-Derived Growth Factor; D013777:Tetrazoles; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D000077405:Irbesartan