Glomerular structural and functional changes in a high-fat diet mouse model of early-stage Type 2 diabetes

Abstract

Aims/hypothesis. Type 2 diabetes often results in diabetic nephropathy, which is preceded by an elevated glomerular filtration rate (GFR). This study was designed to develop a mouse model of Type 2 diabetes and to elucidate the glomerular events in the early stages of diabetic nephropathy. Methods. Four-week-old mice were fed a normal or high-fat (42% of total calories from fat) diet, and body weight, blood glucose, insulin, leptin, lipids and GFR were monitored from 9 to 21 weeks or longer after the feeding programme. Mesangial cell dedifferentiation was accessed by alpha-smooth muscle actin staining. Glomerular hypertrophy was determined using image analysis with haematoxylin-eosin staining. Matrix deposition was determined by type IV collagen staining. Results. After 9 weeks, mice fed a high-fat diet weighed more than mice fed a normal diet (30.5±1.2 vs 22.3±0.5 g, p<0.05), and mice fed a high-fat diet were hyperinsulinaemic (283.9±69.7 vs 102.9±36.4 pmol/l, p<0.05), hyperglycaemic (8.0±0.6 vs 6.5±0.2 mmol/l, p<0.05) and their leptin levels were increased six-fold (1.48±0.45 vs 0.25±0.03 ng/ml, p<0.05). After 13 weeks, mice fed a high-fat diet showed hyperfiltration (GFR; 440±60 vs 210±10 µl/min, p<0.05). During the early stages of diabetic nephropathy, mesangial cell dedifferentiation was evident, shown by increased expression of alpha-smooth muscle actin in the glomeruli. After 9 weeks, mice fed a high-fat diet already demonstrated increased type IV collagen deposition. After 13 weeks, they developed enlarged glomerular tufts compared with those of their age-matched controls. Conclusions/interpretation. The results of this study suggest that collagen IV deposition precedes the hyperfiltration and enlargement of glomeruli in early-stage diabetic nephropathy. Dedifferentiation of mesangial cells may be associated with collagen IV deposition.

Accelerated Glucose Intolerance, Nephropathy, and Atherosclerosis in Prostaglandin D2 Synthase Knock-out Mice

“…Nephropathy has been associated with the severity of hyperglycemia, which itself may contribute to early alterations in kidney structure and function, before the clinical detection of diabetes (30,31). Structural changes indicative of diabetic nephropathy, such as glomerular hypertrophy, fibrosis, and basement membrane thickening, were observed in the L-PGDS KO mice on the low fat diet and were further exacerbated on the diabetogenic diet (Fig.…”

Severe Insulin Resistance and Moderate Glomerulosclerosis in a Minipig Model Induced by High-Fat/ High-Sucrose/ High-Cholesterol Diet

“…It has been shown by several groups that type 2 diabetes can be induced in the mouse [19], rat [5], hamster [16] and minipigs [8,20] by diabetogenic diet enriched in high-fat and high-energy. High saturated fat also induced type 2 diabetes and diabetic nephropathy in C57BL/6J mice [17] and Golden Syrian hamsters [12]. Diet-induced hypercholesterolaemia developed renal injury in rats and domestic crossbred pigs [6,18].…”

PARP1 deficiency exacerbates diet-induced obesity in mice

“…Some inbred strains of mice vary in their susceptibility to diet-induced obesity indicating that obesity is a complex trait and modifications of multiple genes may be necessary for its etiology (Surwit et al 1995, Brockmann & Bevova 2002. We and others have recently reported that C57BL/6 mice are readily susceptible to diet-induced obesity and associated type 2 diabetes (Surwit et al 1988, Wei et al 2004, while the 129 mouse strain is shown to be resistant to diet-induced obesity and insulin resistance (Almind & Kahn 2004, Ishimori et al 2004. Genetic analysis by various groups using cross between different mouse strains has identified more than 100 chromosomal loci, some loci representing high number of genes with differential expression, that may contribute to obesity (Brockmann & Bevova 2002, Almind & Kahn 2004, Ishimori et al 2004.…”