Diabetes-induced Alterations in Renal Microcirculation and Metabolism

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: Diabetes-induced renal complications, i.e. diabetes nephropathy, are a major cause of morbidity and mortality. The exact mechanism mediating the negative influence of hyperglycaemia on renal function is unclear, although several hypotheses have been postulated. Glucose-induced excessive formation of reactive oxygen species (ROS) and increased glucose flux through the polyol pathway are two major mechanisms that have recently gained increasing support. In order to investigate the development of hyperglycaemia-induced renal alterations further, it is of great importance to use an animal model in agreement with the pathological development in diabetic patients.The aims of these investigations were to evaluate the streptozotocin (STZ)-diabetic Wistar Furth rat as a model for human diabetic nephropathy and to investigate involvement of ROS and the polyol pathway in development of diabetes-induced renal alterations.The used STZ-diabetic animal model displayed several similarities with the progression of human disease, including initial hyperfiltration and albuminuria. However, the observed proteinuria could be partly linked to the STZ treatment per se, making the use of this animal model less suitable for research concerning diabetes-induced urinary protein leakage.The diabetic state induced numerous alterations in renal function and metabolism, including increased oxygen consumption, decreased renal oxygen tension (pO2), and altered lactate/pyruvate ratio. These renal alterations were preventable by daily treatment with either a radical scavenger (?-tocopherol) or an aldose reductase inhibitor (AL-1576).In separate experiments the influence of nitric oxide (NO) on renal blood perfusion and pO2 was investigated. The diabetic animals displayed a larger increase in renal NO activity after injecting the NO substrate L-arginine compared to non-diabetic animals, suggesting substrate limitation of the nitric oxide synthase during chronic hyperglycaemia.In conclusion, the results from these investigations show that both ROS and the polyol pathway are involved in the development of diabetes-induced renal alterations in the STZ- diabetic Wistar Furth rat.