title: Diabetic kidney lesions of GIPRdn transgenic mice: podocyte hypertrophy and thickening of the GBM precede glomerular hypertrophy and glomerulosclerosis.
abstract: Diabetic nephropathy is the leading cause of end-stage renal disease and the largest contributor to the total cost of diabetes care. Rodent models are excellent tools to gain more insight into the pathogenesis of diabetic nephropathy. In the present study, we characterize the age-related sequence of diabetes-associated kidney lesions in GIPR(dn) transgenic mice, a novel mouse model of early-onset diabetes mellitus. Clinical-chemical analyses as well as qualitative and quantitative morphological analyses of the kidneys of GIPR(dn) transgenic animals and nontransgenic littermate controls were performed at 3, 8, 20, and 28 wk of age. Early renal changes of transgenic mice consisted of podocyte hypertrophy, reduced numerical volume density of podocytes in glomeruli, and homogenous thickening of the glomerular basement membrane, followed by renal and glomerular hypertrophy as well as mesangial expansion and matrix accumulation. At 28 wk of age, glomerular damage was most prominent, including advanced glomerulosclerosis, tubulointerstitial lesions, and proteinuria. Real-time PCR demonstrated increased glomerular expression of Col4a1, Fn1, and Tgfb1. Immunohistochemistry revealed increased mesangial deposition of collagen type IV, fibronectin, and laminin. The present study shows that GIPR(dn) transgenic mice exhibit renal changes that closely resemble diabetes-associated kidney alterations in humans. Data particularly from male transgenic mice indicate that podocyte hypertrophy is directly linked to hyperglycemia, without the influence of mechanical stress. GIPR(dn) transgenic mice are considered an excellent new tool to study the mechanisms involved in onset and progression of diabetic nephropathy.
authors.affiliation: Institute of Veterinary Pathology, Veterinaerstr. 13, 80539 Munich, Germany. herbach@patho.vetmed.uni-muenchen.de
authors.forename: Nadja
authors.initials: N
authors.lastname: Herbach
authors.forename: Irene
authors.initials: I
authors.lastname: Schairer
authors.forename: Andreas
authors.initials: A
authors.lastname: Blutke
authors.forename: Sabine
authors.initials: S
authors.lastname: Kautz
authors.forename: Angela
authors.initials: A
authors.lastname: Siebert
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Ruediger
authors.initials: R
authors.lastname: Wanke
mesh_terms: D000367:Age Factors; D000419:Albuminuria / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D001835:Body Weight; D031204:Caloric Restriction; D024141:Collagen Type IV / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D050533:Glomerular Basement Membrane / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006984:Hypertrophy; D007797:Laminin / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009929:Organ Size; D050199:Podocytes / Q000378:metabolism / Q000473:pathology*; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D024141:Collagen Type IV; D005353:Fibronectins; D007797:Laminin; D011964:Receptors, Gastrointestinal Hormone; D053773:Transforming Growth Factor beta1; C041086:gastric inhibitory polypeptide receptor