Diabetic nephropathy is now the most common cause of end-stage renal disease in the United States. Our understanding of the pathogenesis of this disorder is limited, in part because a reproducible, easily available animal model of diabetes that manifests the full constellation of glomerular, tubular, and vascular alterations that characterize DN has not yet been identified. Development of lesions resembling diabetic vascular disease, in particular, has been difficult to achieve in any animal model recognized currently. In this application, we take advantage of recent developments in modifying the genetic background of mice. We do so by studying the effects of inducing diabetes in mice genetically manipulated to render them hyperlipidemic and prone to the development of artherosclerosis, one of the principal vascular abnormalities of diabetes. Diabetes will be induced by administration of a chemical toxin, stretozoticin, to insulin producing islet cells of the pancreas or by crossbreeding hyperlipidemic animals which include strains which are deficient in apolipoprotein E and the low density lipoprotein receptor as a result of prior targeted mutations. Functional assessment of ensuring renal injury will include urinary measurements of protein excretion and serum measurements of normally excreted substances such as creatinine and urea nitrogen. Morphological characterization of renal alterations include measures of histologic damage, ultrastructural assessment of glomerular structure and basement membranes that may resemble human DN, and assays for production of several growth factors and their receptors which, based on earlier work, are likely to mediate renal injury in diabetes. By creating diabetes in animal models already known to develop some features of vascular disease similar to that encountered in diabetic patients, we believe a better model for DN can be created. Such models, in an easily studied species such as the mouse, should greatly facilitate efforts to understand the pathogenesis of DN and provide a system to test potentially useful therapeutic interventions for this disease.
