The antioxidant effect of angiotensin II receptor blocker, losartan, in streptozotocin-induced diabetic rats.
We determined the effect of a short-term angiotensin II signaling blockade on vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule-1 (sICAM-1), nitric oxide (NO), and malondialdehyde (MDA) (index of lipid peroxidation) levels in the systemic circulation and on peroxynitrite generation and insulitis development in the streptozotocin (STZ) diabetic rats' pancreas. Diabetes was induced in Wistar rats by intraperitoneal STZ injection. Diabetic rats were treated for 1 week with losartan (20 mg/kg/body weight/day in the drinking water), and pancreas and blood were collected for histochemical, immunohistochemical, and biochemical studies. Diabetic rats showed greater VEGF, sICAM-1, NO, and MDA levels, a high score of insulitis, increased nitrotyrosine staining, and markedly reduced pancreatic insulin content when compared with controls. Losartan treatment suppressed the excessive NO and lipid peroxidation production systemically without restoring them to that of healthy subjects and reduced VEGF levels while leaving sICAM-1 levels unchanged. The insulitis score and nitrotyrosine staining were reduced, whereas the pancreatic islets and the beta-cell area were increased significantly in the treated group, indicating the reduction of inflammation and nitrosative stress and an early regeneration of beta-cell mass in the pancreas. Conclusively, in the STZ diabetic rat model, even a short-term losartan treatment improves oxidative and nitrosative stress systemically and locally, improving the islets' environment and accelerating beta-cell regeneration.
Kamper
Maria
M
Department of Experimental Physiology, Medical School, University of Athens, GR-115 27, Athens, Greece. ekamper@med.uoa.gr
Tsimpoukidi
Olia
O
Chatzigeorgiou
Antonios
A
Lymberi
Maria
M
Kamper
Elli F
EF
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D009566:Nitrates / Q000097:blood / Q000378:metabolism; D009569:Nitric Oxide / Q000097:blood; D010179:Pancreas / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D001786:Blood Glucose; D009566:Nitrates; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D008315:Malondialdehyde; D013311:Streptozocin; D019808:Losartan