RESUMO
The pathogenesis of diabetic nephropathy remains far from clear, partly due to the lack of a suitable animal model that mimics human renal disease in type 2 diabetes. In this study, the natural history of renal manifestations in ZSF1 rats, a recently developed rodent model of type 2 diabetes, is described. Male ZSF1 rats developed obesity and hyperglycemia by 20 weeks of age on a high-carbohydrate diet. They also developed systolic and diastolic hypertension, hypercholesterolemia, profound hypertriglyceridemia, proteinuria, and renal failure. Renal histology demonstrated changes consistent with early diabetic nephropathy, including arteriolar thickening, tubular dilation and atrophy, glomerular basement membrane thickening, and mesangial expansion. Furthermore, renal nitric oxide production was decreased, and homogenates from renal cortices demonstrated reduced expression of renal endothelial and inducible nitric oxide synthases. These changes were associated with increased urinary levels and renal expression of 8-hydroxydeoxyguanosine, an indicator of mitochondrial oxidative stress, as well as with increased renal peroxynitrite formation. Administration of either insulin or the antioxidant alpha-lipoic acid decreased proteinuria and oxidative stress, but only the former slowed progression of renal failure. We conclude that ZSF1 rats represent the best available rat model to study nephropathy from type 2 diabetes and that the renal lesions are associated with increased oxidative stress and decreased renal nitric oxide availability.
Assuntos
Nefropatias Diabéticas/etiologia , Modelos Animais de Doenças , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , 8-Hidroxi-2'-Desoxiguanosina , Animais , Animais Geneticamente Modificados , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Feminino , Taxa de Filtração Glomerular , Mesângio Glomerular/patologia , Falência Renal Crônica/etiologia , Falência Renal Crônica/metabolismo , Falência Renal Crônica/prevenção & controle , Masculino , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos EndogâmicosRESUMO
Exhaled nitric oxide has been used as a means of indirectly measuring the underlying inflammation in asthma. The objectives of the study were to measure exhaled nitric oxide levels in asthma patients and healthy volunteers, to study peripheral blood lymphocyte cytokine expression, and to study the relationship between exhaled nitric oxide and intracellular cytokine expression. Exhaled nitric oxide was elevated in patients with moderate to severe asthma and with treatment decreased in the first week reaching to a near normal level by 4 weeks. Elevated exhaled nitric oxide was associated with decreased IL-4 and IL-13 cytokine expression by CD8 lymphocytes.