A model for diabetic nephropathy: Advantages of the inducible cAMP early repressor transgenic mouse over the streptozotocin-induced diabetic mouse (original) (raw)
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Establishment of a Diabetic Mouse Model with Progressive Diabetic Nephropathy
The American Journal of Pathology, 2005
Although diabetic animal models exist, no single animal model develops renal changes identical to those seen in humans. Here we show that transgenic mice that overexpress inducible cAMP early repressor (ICER I␥) in pancreatic  cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER I␥ transgenic mice exhibit extremely high blood glucose levels throughout their lives, they survive long enough to develop diabetic nephropathy. Using this model we followed the progress of diabetic renal changes compared to those seen in humans. By 8 weeks of age, the glomerular filtration rate (GFR) was already increased, and glomerular hypertrophy was prominent. At 20 weeks, GFR reached its peak, and urine albumin excretion rate was elevated. Finally, at 40 weeks, diffuse glomerular sclerotic lesions were prominently accompanied by increased expression of collagen type IV and laminin and reduced expression of matrix metalloproteinase-2. Nodular lesions were absent, but glomerular basement membrane thickening was prominent. At this point, GFR declined and urinary albumin excretion rate increased, causing a nephrotic state with lower serum albumin and higher serum total cholesterol. Thus, similar to human diabetic nephropathy, ICER I␥ transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors.
Scientific Reports, 2018
Diabetic nephropathy (DN) is the leading cause of chronic kidney disease. Animal models are essential tools for designing new strategies to prevent DN. C57Bl/6 (B6) mice are widely used for transgenic mouse models, but are relatively resistant to DN. This study aims to identify the most effective method to induce DN in a type 1 (T1D) and a type 2 diabetes (T2D) model in B6 mice. For T1D-induced DN, mice were fed a control diet, and randomised to streptozotocin (STZ) alone, STZ+unilateral nephrectomy (UNx), or vehicle/sham. For T2D-induced DN, mice were fed a western (high fat) diet, and randomised to either STZ alone, STZ+UNx, UNx alone, or vehicle/sham. Mice subjected to a control diet with STZ +UNx developed albuminuria, glomerular lesions, thickening of the glomerular basement membrane, and tubular injury. Mice on control diet and STZ developed only mild renal lesions. Furthermore, kidneys from mice on a western diet were hardly affected by diabetes, UNx or the combination. We co...
A novel mouse model of diabetes mellitus using unilateral nephrectomy
Laboratory animals, 2015
Diabetes mellitus (DM) is a major cause of morbidity and mortality worldwide, and its complications are prominent public health issues. Many experimental models of streptozotocin (STZ)-induced and high-fat diet (HF)-induced DM have been used to study this disease. Studies have indicated that unilateral nephrectomy (UN) accelerates the development of diabetic nephropathy. We hypothesized that UN stimulates HF and STZ combination-induced DM in mice. Seventy-two female C57BL/6J mice were divided into four treatment groups: HF; HF + STZ120 (HF and STZ, 120 mg/kg); UN + HF + STZ120 (UN, HF and STZ, 120 mg/kg); and HF + STZ200 (HF and STZ, 200 mg/kg). Onset of DM, survival rate, blood pressure, urine glucose level, and pancreatic histology were investigated. Additionally, renal function was evaluated in the UN + HF + STZ120 group after STZ injection. DM was induced in the UN + HF + STZ120 and HF + STZ200 groups within one week. The UN + HF + STZ120 group had lower mortality than the HF + ...
Rodent animal models: from mild to advanced stages of diabetic nephropathy
Inflammopharmacology, 2014
Diabetic nephropathy (DN) is a secondary complication of both type 1 and type 2 diabetes, resulting from uncontrolled high blood sugar. 30-40 % of diabetic patients develop DN associated with a poor life expectancy and end-stage renal disease, causing serious socioeconomic problems. Although an exact pathogenesis of DN is still unknown, several factors such as hyperglycemia, hyperlipidemia, hypertension and proteinuria may contribute to the progression of renal damage in diabetic nephropathy. DN is confirmed by measuring blood urea nitrogen, serum creatinine, creatinine clearance and proteinuria. Clinical studies show that intensive control of hyperglycemia and blood pressure could successfully reduce proteinuria, which is the main sign of glomerular lesions in DN, and improve the renal prognosis in patients with DN. Diabetic rodent models have traditionally been used for doing research on pathogenesis and developing novel therapeutic strategies, but have limitations for translational research. Diabetes in animal models such as rodents are induced either spontaneously or by using chemical, surgical, genetic, or other techniques and depicts many clinical features or related phenotypes of the disease. This review discusses the merits and demerits of the models, which are used for many reasons in the research of diabetes and diabetic complications.
Journal of diabetes research, 2016
Type 2 diabetes (DM2) could be reproduced in rats with alimentary obesity by using low doses of streptozotocin (LD-STZ) as well as STZ in high doses with preliminary nicotinamide (NA) administration. However, STZ could induce tubulotoxicity. Aim. To develop rat model of DN in NA-STZ-induced DM2 and compare it with LD-STZ-model in order to choose the most relevant approach for reproducing renal glomerular and tubular morphofunctional diabetic changes. Starting at 3 weeks after uninephrectomy, adult male Wistar rats were fed five-week high-fat diet and then received intraperitoneally either LD-STZ (40 mg/kg) or NA (230 mg/kg) followed by STZ (65 mg/kg). Control uninephrectomized vehicle-injected rats received normal chow. At weeks 10, 20, and 30 (the end of the study), metabolic parameters, creatinine clearance, albuminuria, and urinary tubular injury markers (NGAL, KIM-1) were evaluated as well as renal ultrastructural and light microscopic changes at weeks 20 and 30. NA-STZ-group sh...
Mouse models of diabetic nephropathy
Current Opinion in Nephrology and Hypertension, 2011
Purpose-Progress in identification of effective therapies for diabetic nephropathy continues to be limited by the lack of ideal animal models. Here we review the current status of some leading murine models of this disorder.
Kidney involvement in a nongenetic rat model of type 2 diabetes
Kidney International, 2005
Background. Rats fed a high fat diet and given a low dose of streptozotocin (STZ) (35 mg/kg) develop type 2 diabetes with insulin resistance, hyperinsulinemia, moderate hyperglycemia, hyperlipidemia, and salt-sensitive hypertension. We postulated that rats with noninsulinopenic (type 2) diabetes develop lesions of diabetic nephropathy significantly more prominent than those seen in classic insulinopenic (type 1) diabetic rats.