title: Establishment of a diabetic mouse model with progressive diabetic nephropathy.
abstract: 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 Igamma) in pancreatic beta cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER Igamma 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 Igamma transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors.
authors.affiliation: Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Akari
authors.initials: A
authors.lastname: Inada
authors.forename: Kojiro
authors.initials: K
authors.lastname: Nagai
authors.forename: Hidenori
authors.initials: H
authors.lastname: Arai
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Keiko
authors.initials: K
authors.lastname: Nomura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kanamori
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Weir
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukatsu
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Seino
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D024141:Collagen Type IV / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator; D004268:DNA-Binding Proteins / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005919:Glomerular Filtration Rate; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology; D006984:Hypertrophy; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology*; D007797:Laminin / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000418:Albumins; D001786:Blood Glucose; D024141:Collagen Type IV; D004268:DNA-Binding Proteins; D007328:Insulin; D007797:Laminin; D012097:Repressor Proteins; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator; D002784:Cholesterol; D020778:Matrix Metalloproteinase 2