SUMMARY:Streptozotocin-induced pancreatic injury is commonly used for creating rodent models of type 1 diabetes which develop renal injury with similarities to human diabetic nephropathy. This model can be established in genetically modified rodents for investigating the role of molecular mechanisms and genetic susceptibility in the development of diabetic nephropathy. In this report, the authors describe and compare the current protocols being used to establish models of diabetic nephropathy in rat and mouse strains using streptozotocin. The authors also list some of the histological criteria and biochemical measurements which are being used to validate these models. In addition, our review explains some of the key aspects involved in these models, including the impact of streptozotocin-dosage, uninephrectomy, hypertension and genetically modified strains, which can each affect the development of disease and the interpretation of findings. KEY WORDS: diabetic nephropathy, mouse, rat, streptozotocin.Diabetic nephropathy is clinically defined as the progressive development of renal insufficiency in the setting of hyperglycaemia. This disease is now the major single cause of end stage renal failure in many countries. Reliable animal models of diabetic renal injury are a valuable tool for identifying the molecular mechanisms responsible for this disease and for the preclinical development of new therapeutic strategies. Recently, a number of genetically modified (knockout and transgenic) mouse strains have been used to provide important insights into the roles of oxidative stress, advanced glycation end products, inflammation and profibrotic mechanisms in the development of diabetic nephropathy.Chemical agents, such as streptozotocin (STZ) and alloxan, that can selectively damage the insulin-producing b-cells in the pancreas resulting in hyperglycaemia, are important tools for developing animal models of diabetic complications. These reagents can be used to study diabetic tissue injury in most rodent strains, although the severity of injury is partly dependent on genetic background. Models that use STZ to induce type 1 diabetes, have been shown to develop modest elevations in albuminuria and serum creatinine and some of the histological lesions associated with diabetic nephropathy. Obtaining meaningful data from such models is dependent on various factors, including: (i) a reliable method for establishing a consistent level of diabetes; (ii) being able to maintain a steady level of diabetes for the duration of the experiment; (iii) understanding the disease characteristics and progression of injury in the rodent strain being used; and (iv) the achievement of a pathological state which has clinical relevance. In order to assist researchers, this paper provides a description of current protocols and key issues for developing a rodent model of STZ-induced diabetic renal injury. MATERIALS AND REAGENTSThe following items are required to establish a rodent model of STZ-induced diabetes (Table 1). METHODS Preparation and s...

Background-Atherosclerosis is a major complication of diabetes, but the mechanisms by which diabetes promotes macrovascular disease have not been fully delineated. Although several animal studies have demonstrated that inhibition of ACE results in a decrease in the development of atherosclerotic lesions, information about the potential benefits of these agents on complex and advanced atherosclerotic lesions as observed in long-term diabetes is lacking. The aim of this study was to evaluate whether treatment with the ACE inhibitor perindopril affects diabetes-induced plaque formation in the apolipoprotein E (apoE)-deficient mouse. Methods and Results-Diabetes was induced by injection of streptozotocin in 6-week-old apoE-deficient mice. Diabetic animals received treatment with perindopril (4 mg · kg Ϫ1 · d

Advanced glycation end product (AGE) formation may contribute to the progression of atherosclerosis, particularly in diabetes. The present study explored atherosclerosis in streptozotocin-induced diabetic apolipoprotein E-deficient (apoE؊/؊) mice that were randomized (n ‫؍‬ 20) to receive for 20 weeks no treatment, the AGE cross-link breaker ALT-711, or the inhibitor of AGE formation aminoguanidine (AG). A sixfold increase in plaque area with diabetes was attenuated by 30% with ALT-711 and by 40% in AG-treated mice. Regional distribution of plaque demonstrated no reduction in plaque area or complexity within the aortic arch with treatment, in contrast to the thoracic and abdominal aortas, where significant attenuation was seen. Diabetes-associated accumulation of AGEs in aortas and plasma and decreases in skin collagen solubility were ameliorated by both treatments, in addition to reductions in the vascular receptor for AGE. Collagenassociated reductions in the AGEs carboxymethyllysine and carboxyethyllysine were identified with both treatments. Diabetes was also accompanied by aortic accumulation of total collagen, specifically collagens I, III, and IV, as well as increases in the profibrotic cytokines transforming growth factor-␤ and connective tissue growth factor and in cellular ␣-smooth muscle actin. Attenuation of these changes was seen in both treated diabetic groups. ALT-711 and AG demonstrated the ability to reduce vascular AGE accumulation in addition to attenuating atherosclerosis in these diabetic mice.