Pharmacological Research 65 (2012) 465–471 Contents lists available at SciVerse ScienceDirect Pharmacological Research jo ur n al hom epage: www.elsevier.com/locate/yphrs The protective effect of losartan in the nephropathy of the diabetic rat includes the control of monoamine oxidase type A activity Maria Elena Manni 1 , Elisabetta Bigagli 1 , Maura Lodovici, Marina Zazzeri, Laura Raimondi ∗ Department of Pharmacology, University of Florence, Viale G. Pieraccini, 6, 50139 Florence, Italy a r t i c l e i n f o Article history: Received 19 September 2011 Received in revised form 14 November 2011 Accepted 14 November 2011 Keywords: Rat diabetic nephropathy Monoamine oxidase activity type A Superoxide dysmuthase Oxidative stress Catalase Losartan a b s t r a c t 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 acethyl- glucosaminidase and -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 -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 -GGT, reduce oxidative attack to tubular cells. © 2011 Elsevier Ltd. All rights reserved. 1. Introduction Monoamine oxidases (MAO; EC 1.4.3.4) are ubiquitously expressed FAD-dependent enzymes, localized at the outer mito- chondrial membrane of which two isoforms, MAO-A and B, with peculiar tissue distribution, substrate selectivity and inhibitor specificity are known [1]. Amongst MAO-A endogenous substrates are noradrenaline and serotonin while dopamine is a common MAO-A and B substrate. The oxidative deamination of these amines does cause the production of hydrogen peroxide (H 2 O 2 ), the amine corresponding aldehyde and ammonia. Because of this, MAO activ- ity has recently been growingly studied as a new endogenous source of reactive oxygen (ROS) and carbonyl species which may participate in unbalancing cell redox state. In this respect, evi- dence demonstrated that, in the kidney and in the heart of rodents, MAO-A activity does play a determinant role in ROS-dependent ischemia reperfusion injuries and in tissue hypertrophy [2–4]. This evidence suggests that MAO activity might have a role in ∗ Corresponding author. Tel.: +39 5 5427 1210; fax: +39 5 5427 1288. E-mail address: laura.raimondi@unifi.it (L. Raimondi). 1 These authors contributed equally to this work. many other chronic pathological conditions, characterized by tis- sue redox unbalance, with concurrence of diabetic nephropathy (DN), a long-term microvascular complication and leading cause of morbidity and mortality of diabetic patients [5]. DN is character- ized by glomerular hypertrophy and fibrosis, mesangial expansion, podocyte loss and vascular endothelial dysfunction progressively leading to glomerulosclerosis, tubulointerstitial fibrosis and pro- teinuria which does represent the early clinical manifestation of the disease recognized as a new cardiovascular risk factor [6]. The balance between natriuretic and anti-natriuretic hormones plays a critical role in the regulation of renal sodium transport and excretion [7]. In the adult kidney, through the stimulation of AT1 receptors, angiotensin-II performs actions which are opposed to those elicited by dopamine (DA). While DA stimulates natriure- sis, angiotensin-II diminishes diuresis and natriuresis and increases blood pressure [8] so that the interplay between these two hor- mones represents an important mechanism for the regulation of renal sodium and water excretion. Experimental evidence has shown that, in the central nervous system [9], as well as in the kidney of rodents, angiotensin- II, by activating AT1, increases MAO activity thus enhancing DA metabolism [10]. These results designate MAO activity as a crossover of an intriguing relationship between dopamine and 1043-6618/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2011.11.010