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(American Journal of Pathology. 2005;167:327-336.)
© 2005 American Society for Investigative Pathology

Establishment of a Diabetic Mouse Model with Progressive Diabetic Nephropathy

Akari Inada^*, Kojiro Nagai, Hidenori Arai, Jun-ichi Miyazaki, Keiko Nomura^¶, Hiroshi Kanamori, Shinya Toyokuni^||, Yuichiro Yamada^*, Susan Bonner-Weir, Gordon C. Weir, Atsushi Fukatsu^¶ and Yutaka Seino^***

From the Departments of Diabetes and Clinical Nutrition,^* Geriatric Medicine, Nephrology,^¶ and Pathology and Biology of Disease,|| Kyoto University Graduate School of Medicine, Kyoto, Japan; the Division of Stem Cell Regulation Research G6, Medical School, Osaka University, Suita, Osaka, Japan; Kansai Denryoku Hospital,^** Osaka, Japan; and the Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts

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 ß 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.

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