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

P. Wei, P. H. Lane, J. T. Lane, B. J. Padanilam, S. C. Sansom

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58 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1541-1549
Number of pages9
JournalDiabetologia
Volume47
Issue number9
DOIs
Publication statusPublished - Sep 1 2004

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Keywords

  • Diabetic nephropathy
  • GFR
  • Glomerulopathy
  • High-fat diet
  • Hyperfiltration
  • Hyperglycaemia
  • Hyperinsulinaemia
  • Leptin
  • Mice
  • Obesity
  • Type 2 diabetes
  • Type IV collagen

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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