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

Diabetologia. 2004 Sep;47(9):1541-9. doi: 10.1007/s00125-004-1489-1. Epub 2004 Aug 27.

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 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/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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Body Weight
  • Cell Differentiation
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / pathology*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Dietary Fats*
  • Disease Models, Animal
  • Insulin / blood
  • Kidney Glomerulus / pathology*
  • Kidney Glomerulus / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Weight Gain

Substances

  • Blood Glucose
  • Dietary Fats
  • Insulin