The protective effect of losartan in the nephropathy of the diabetic rat includes the control of monoamine oxidase type A activity

Monoamine oxidase activity (MAO-A and B) levels, as intracellular source of reactive oxygen species, might increase in diabetic nephropathy (DN) contributing to reduce dopamine levels and to unbalance kidney redox state. We explored the hypothesis that beneficial effects of losartan, an angiotensin-II type 1 receptor (AT1) blocker, in DN included the control of MAO activity levels.In kidneys of normoglycemic and diabetic, streptozotocin-injected (55 mg/kg) rats, treated or untreated with losartan, an AT1 antagonist (20 mg/kg/day in the drinking water), we investigated MAO activity radiochemically and antioxidant enzymes including catalase, aldehyde dehydrogenase and superoxide dysmuthase spectrophotometrically. In addition, we also evaluated malondialdehyde and carbonylated protein levels spectrophotometrically as indexes of oxidative attack to lipids and proteins.Diabetic rats showed signs of nephropathy, including renal hypertrophy, proteinuria, high acethylglucosaminidase and γ-glutamyltranspeptidase urinary levels. In diabetic kidneys, MAO-A and catalase activities as well as malondialdehyde levels, were found significantly higher than in normoglycemic ones. Interestingly, in diabetic kidneys, MAO-A activity correlated not only with catalase but also with γ-glutamyltranspeptidase urinary levels.Our results indicate that the control of MAO-A activity is to be included amongst the mechanisms of protection afforded by losartan in DN. In fact, the prevention of MAO-A raise might increase dopamine availability and, as suggested by the correlation with γ-GGT, reduce oxidative attack to tubular cells.

Angiogensin-II and dopamine exert opposite effects on natriuresis. In the diabetic kidney, natriuresis is compromised by reduced dopamine and increased angiotensin-II tissue levels. We have demonstrated that angiotensin-II, by activating type 1 receptor (AT1), is responsible for increasing monoamine oxidase type A activity (MAO-A), the enzyme degrading dopamine producing reactive oxygen species (ROS). Unbalanced kidney redox state is amongst the pathogenic factors responsible for proteinuria and tubular injuries. In line with this, ROS produced by MAO activity induce an antioxidant compensatory response evident in the increase of catalase (CAT) activity and with the positive correlation between MAO-A and urinary levels of γ-glutamyltransferase (γ-GTT). The treatment of diabetic rats with losartan, an AT1 antagonist, ameliortaes kidney nephrophaty indexes including proteinuria. The prevention of MAO-A increase participates to this protection. In fact, in the kidney from diabetic rats treated with losartan, MAO-A and CAT activities and lipoperoxidation levels were similar to those found in normoglycemic kidney and no correlation between MAO-A and urinay γ-GGT levels were found. These results add further information on the “antioxidant” features of losartan and on its mechanism of protection in the diabetic kidney.Figure optionsDownload high-quality image (99 K)Download as PowerPoint slide