Glomerular structural and functional changes in a high-fat diet mouse model of early-stage Type 2 diabetes.
OBJECTIVE
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 microl/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
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.
Wei
P
P
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Lane
P H
PH
Lane
J T
JT
Padanilam
B J
BJ
Sansom
S C
SC
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002454:Cell Differentiation; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000473:pathology* / Q000503:physiopathology; D004041:Dietary Fats; D004195:Disease Models, Animal; D007328:Insulin / Q000097:blood; D007678:Kidney Glomerulus / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015430:Weight Gain
D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin