Targeting the superoxide/nitric oxide ratio by L-arginine and SOD mimic in diabetic rat skin

Setting the correct ratio of superoxide anion (O-2(center dot)) and nitric oxide ((NO)-N-center dot) radicals seems to be crucial in restoring disrupted redox signaling in diabetic skin and improvement of (NO)-N-center dot physiological action for prevention and treatment of skin injuries in diabetes. In this study we examined the effects of L-arginine and manganese(II)-pentaazamacrocyclic superoxide dismutase (SOD) mimic - M40403 in diabetic rat skin. Following induction of diabetes by alloxan (blood glucose level >= 12 mMol l(-1)) non-diabetic and diabetic male Mill Hill hybrid hooded rats were divided into three subgroups: (i) control, and receiving: (ii) L-arginine, (iii) M40403. Treatment of diabetic animals started after diabetes induction and lasted for 7 days. Compared to control, lower cutaneous immuno-expression of endothelial NO synthase (eNOS), heme oxygenase 1 (HO1), manganese SOD (MnSOD) and glutathione peroxidase (GSH-Px), in parallel with increased NFE2-related factor 2 (Nrf2) and nitrotyrosine levels characterized diabetic skin. L-arginine and M40403 treatments normalized alloxan-induced increase in nitrotyrosine. This was accompanied by the improvement/restitution of eNOS and HO1 or MnSOD and GSH-Px protein expression levels in diabetic skin following L-arginine, i.e. SOD mimic treatments, respectively. The results indicate that L-arginine and M40403 stabilize redox balance in diabetic skin and suggest the underlying molecular mechanisms. Restitution of skin redox balance by L-arginine and M40403 may represent an effective strategy to ameliorate therapy of diabetic skin.