Regression of glomerular injury by losartan in experimental diabetic nephropathy.

Many features of chronic kidney disease may be reversed, but it is unclear whether advanced lesions, such as adhesions of sclerotic glomerular tufts to Bowman's capsule (synechiae), can resolve during treatment. We previously showed, using a renal ablation model, that the renoprotective effect of the AT-1 receptor blocker, losartan, is dose-dependent. Here we determined if moderate and advanced glomerular lesions, associated with streptozotocin-induced diabetes, regress with conventional or high-dose losartan treatment. Using daily insulin injection for 10 months, we maintained diabetic adult male Munich-Wistar rats in a state of moderate hyperglycemia. Following this period, some rats continued to receive insulin with or without conventional or high-dose losartan for an additional 2 months. Diabetic rats pretreated with insulin for 10 months and age-matched non-diabetic rats served as controls. Mesangial expansion was found in the control diabetic rats and was exacerbated in those rats maintained on only insulin for an additional 2 months. Conventional and high-dose losartan treatments reduced this mesangial expansion and the severity of synechiae lesions below that found prior to treatment; however, the frequency of the latter was unchanged. There was no dose-response effect of losartan. Our results show that regression of mesangial expansion and contraction of sclerotic lesions is feasible in the treatment of diabetes, but complete resolution of advanced glomerulosclerosis may be hard to achieve.

Effects of a chronic exercise training protocol on oxidative stress and right ventricular hypertrophy in monocrotaline-treated rats.

1. In the present study, we investigated the effects of exercise training on cardiac hypertrophy and oxidative stress in a monocrotaline (MCT)-induced cor pulmonale model. Male Wistar rats were assigned to one of three groups: sedentary control (SC); sedentary MCT (SM); or trained MCT (TM). 2. Right ventricular hypertrophy (RVH) was induced by a single injection of MCT (60 mg/kg, i.p.). Exercise training consisted of running on a treadmill (five times a week, during Weeks 3, 4 and 5). Systemic oxidative stress was evaluated in erythrocytes by chemiluminescence (CL) and the activity of the anti-oxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST) was determined. 3. At Week 3, MCT-treated animals exhibited RVH, lung congestion, decreased SOD activity and increased CAT activity. Exercise training reduced MCT-induced RVH and increased GST activity. At Week 4, MCT-induced RVH was accompanied by an increase in CL and GST activity. However, in TM animals there was a decrease in CL and augmented SOD activity. At Week 5, there were no survivors in the SM group, whereas GST activity was elevated in TM rats compared with SC rats. There was no difference in GPx activity throughout the experimental protocol between the groups. 4. Taken together, our results indicate that exercise training is able to ameliorate RVH and improve survival, which is associated with a reduction in oxidative stress in MCT-treated rats.

Abnormal alveolar attachments with decreased elastic fiber content in distal lung in fatal asthma.

Small airway disease is thought to contribute significantly to functional impairment caused by asthma. Functional evidence of airway-parenchyma uncoupling in asthma, such as loss of deep breath bronchodilator effect in bronchoconstrictive episodes and enhanced airway closure, has been previously demonstrated. Elastic fibers are essential to maintain adequate elastic recoil of the lungs. In this study, we hypothesized that alveolar attachments could be abnormal and that elastic fibers could be damaged in the distal lungs of patients with fatal asthma. For this purpose, we measured the number of abnormal alveolar attachments and quantified the content of elastic fibers in the adventitial layer of small airways and in the peribronchial and distal alveolar septa of 15 patients who died of asthma (FA) and 9 control subjects (CTRL). Our data (geometric mean [range]) showed an increased proportion of abnormal alveolar attachments per centimeter of basement membrane perimeter in fatal asthma (FA, 0.18 [0.03-4.00]; CTRL, 0.00 [0.00-0.12]; p < 0.001) and decreased elastic fiber content in the small airway adventitial layer (FA, 4.08 [2.22-11.46] microm; CTRL, 6.79 [5.62-10.0] microm; p = 0.01) and in the peribronchial alveoli (FA, 1.08 [0.46-1.91] microm; CTRL, 1.81 [1.22-1.74] microm; p = 0.003), but not in the distal alveoli. We propose that structural alterations at the peribronchiolar level might contribute to the pathogenesis of some functional abnormalities observed in patients with severe asthma.