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Am J Physiol Renal Physiol 291: F1315-F1322, 2006. First published May 16, 2006; doi:10.1152/ajprenal.00379.2005
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Characterization of diabetic nephropathy in a transgenic model of hypoinsulinemic diabetes

Yukiko Kanetsuna,1,* Keita Hirano,1,* Michio Nagata,2 Maureen A. Gannon,1 Keiko Takahashi,1 Raymond C. Harris,1 Matthew D. Breyer,1 and Takamune Takahashi1

1Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and 2Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki, Japan

Submitted 21 September 2005 ; accepted in final form 9 May 2006

Genetic mouse models provide a unique opportunity to investigate gene function in the natural course of the disease. Although diabetic nephropathy (DN) in models of type II diabetes has been well characterized, diabetic renal disease in hypoinsulinemic diabetic mice is still incompletely understood. Here, we characterized renal changes in the pdx1PB-HNF6 transgenic mouse that exhibits beta-cell dysfunction and nonobese hypoinsulinemic diabetes. Male transgenic mice developed hyperglycemia by the age of 7 wk and survived for over 1 yr without insulin treatment. Diabetes ensued earlier and progressed more severely in the HNF6 males than the females. The HNF6 males exhibited albuminuria as early as 10 wk of age, and the urinary albumin excretion increased with age, exceeding 150 µg/24 h at 11 mo of age. Diabetic males developed renal hypertrophy after 7 wk of age, whereas glomerular hyperfiltration was not observed in the mice. Hypertension and hyperlipidemia were not observed in the diabetic mice. Histological analysis of the HNF6 kidneys displayed diabetic glomerular changes, including glomerular enlargement, diffuse mesangial proliferation and matrix expansion, thickened glomerular basement membrane, and arteriolar hyalinosis. Mesangial matrix accumulation increased with age, resulting in nodular lesions by 44 wk of age. Immunohistochemistry showed accumulation of type IV collagen and TGF-beta1 in the mesangial area. No significant immune complex deposition was observed in the HNF6 glomeruli. Thus the HNF6 mouse exhibits diabetic renal changes that parallel the early phase of human DN. The model should facilitate studies of genetic and environmental factors that may affect DN in hypoinsulinemic diabetes.

animal model; diabetic renal disease; hepatocyte nuclear factor-6; transgenic mice


Address for reprint requests and other correspondence: T. Takahashi, Dept. of Medicine, Div. of Nephrology and Hypertension, Vanderbilt Univ. Medical Ctr., S-3223, MCN, Nashville, TN 37232 (e-mail: takamune.takahashi{at}vanderbilt.edu)






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