RENAL MITOCHONDRIAL IMPAIRMENT IS ATTENUATED BY AT1-BLOCKADE IN EXPERIMENTAL TYPE I DIABETES Running title: Losartan protects mitochondria in streptozotocin-diabetes

To investigate whether Ang II type-1 (AT1) receptor blockade could protect kidney mitochondria in streptozotocin-induced type-I diabetes, 8-week-old, male Sprague-Dawley rats received: a single streptozotocin injection (65 mg/kg, i.p.) (STZ group); streptozotocin and drinking water containing losartan (30 mg/kg/d) (STZ+Los group), or amlodipine (3 mg/kg/d) (STZ+Amlo group); or saline (i.p.) and pure water (Control group). Four-month long losartan or amlodipine treatments started 30 d prior to streptozotocin injection to improve the antioxidant defenses. Renal lesions, plasma glucose and lipids, and proteinuria were higher, and creatinine clearance was lower in STZ and STZ+Amlo versus STZ+Los and Control. Glycemia was higher in STZ+Los versus Control. Blood pressure, basal mitochondrial membrane potential, mitochondrial pyruvate, and renal oxidized glutathione were higher, and NADH/cytochrome c oxidoreductase activity lower, in STZ versus the other groups. In STZ and STZ+Amlo, mitochondrial H2O2 production rate was higher, and uncoupling protein-2 content, cytochrome c oxidase activity and renal glutathione were lower than in STZ+Los and Control. Mitochondrial nitric oxide synthase activity was higher in STZ+Amlo versus the other groups. Mitochondrial pyruvate and H2O2 production rate negatively contributed to electron transfer capacity, and positively contributed to renal lesions. Uncoupling protein-2 content negatively contributed to mitochondrial H2O2 production rate and renal lesions. Renal glutathione reduction potential positively contributed to mitochondria electron transfer capacity. Concluding, AT1-blockade protects kidney mitochondria and kidney structure in streptozotocin-induced diabetes independently of blood pressure and glycemia. Page 2 of 38 Copyright Information