N-acetylcysteine protects against diabetic nephropathy through control of oxidative and nitrosative stress by recovery of nitric oxide in rats

摘要

The diabetes mellitus (DM) induces several changes, with substantial increase of reactive oxygen species (ROS). The ROS cause damage to systemic and renal microvasculature, which could be one of the mechanisms involved in the development of diabetic nephropathy (DN). The ROS modulate other substances like the nitric oxide (NO), a vasodilator with important role in the renal function. N-acetylcysteine (NAC) is an antioxidant that acts replenishing intracellular cysteine levels, which is essential for glutathione formation. The aim of this study was to evaluate the effect of early or late NAC treatment on oxidative/nitrosative stress in DN progression. All rats were submitted to unilateral nephrectomy and diabetes was induced with streptozotocin. The animals were allocated into six groups: controls that received water (CTL) or NAC (CTL + NAC); diabetic groups that received early or late, water (DM-E; DM-L) or NAC (DM + NAC-E; DM + NAC-L), started on 5th day (early) or 4th week (late) after diabetes induction, during 8 weeks. After NAC treatment, the rats were placed in individual metabolic cages to obtain urine and blood samples for analysis of metabolic profile, renal function, thiobarbituric acid reactive substances (TBARS) and NO. At the end of the protocol, the renal cortex was removed for TBARS, NOS evaluation, antioxidants markers and histology. The DM-E group compared to CTL showed a significant increase in glycemia and proteinuria and impaired renal function; there was a significant increase of TSARS in plasma, urine and renal tissue, and also a significant decrease in plasma NO, which were reverted after early NAC treatment. The eNOS was decreased and iNOS was increased in DM-E vs. CTL, p 0.05. The early NAC treatment in DM rats reduced proteinuria, creatinine, urea, TBARS and iNOS and, increased creatinine clearance, NO and eNOS, increasing significantly the antioxidant defenses, promoting elevated catalase and glutathione compared to DM-E group, all p