Diabetic kidney lesions of GIPRdn transgenic mice: podocyte hypertrophy and thickening of the GBM precede glomerular hypertrophy and glomerulosclerosis

1 Institute of Veterinary Pathology, LMU Munich; 2 Department of Internal Medicine II, Klinikum Grosshadern, LMU Munich; and 3 Chair for Molecular Animal Breeding and Biotechnology/Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, Germany Submitted 10 November 2008 ; accepted in final form 4 February 2009 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. diabetic glomerulosclerosis; animal model Address for reprint requests and other correspondence: N. Herbach, Institute of Veterinary Pathology, Veterinaerstr. 13, 80539 Munich, Germany (e-mail: herbach{at}patho.vetmed.uni-muenchen.de )