Characterization of Susceptibility of Inbred Mouse Strains to Diabetic Nephropathy

Characterization of Susceptibility of Inbred Mouse Strains to Diabetic Nephropathy Zhonghua Qi 1 , Hiroki Fujita 1 , Jianping Jin 1 , Linda S. Davis 1 , Yihan Wang 2 , Agnes B. Fogo 2 and Matthew D. Breyer 1 3 4 1 Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 2 Department of Pathology, Vanderbilt University, Nashville, Tennessee 3 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 4 Veterans Administration Medical Center, Nashville, Tennessee Address correspondence and reprint requests to Zhonghua Qi, MD, F-424 ACRE Building, Veterans Administration Medical Center, Nashville, TN 37212. E-mail: zhonghua.qi{at}vanderbilt.edu Abstract Differential susceptibility to diabetic nephropathy has been observed in humans, but it has not been well defined in inbred strains of mice. The present studies characterized the severity of diabetic nephropathy in six inbred mouse strains including C57BL/6J, DBA/2J, FVB/NJ, MRL/MpJ, A/J, and KK/HlJ mice. Diabetes mellitus was induced using low-dose streptozotocin injection. Progression of renal injury was evaluated by serial measurements of urinary albumin excretion, glomerular filtration rate (GFR), and terminal assessment of renal morphology over 25 weeks. Despite comparable levels of hyperglycemia, urinary albumin excretion and renal histopathological changes were dramatically different among strains. DBA/2J and KK/HlJ mice developed significantly more albuminuria than C57BL/6J, MRL/MpJ, and A/J mice. Severe glomerular mesangial expansion, nodular glomerulosclerosis, and arteriolar hyalinosis were observed in diabetic DBA/2J and KK/HlJ mice. Glomerular hyperfiltration was observed in all diabetic strains studied except A/J. The significant decline in GFR was not evident over the 25-week period of study, but diabetic DBA/2J mice exhibited a tendency for GFR to decline. Taken together, these results indicate that differential susceptibility to diabetic nephropathy exists in inbred mice. DBA/2J and KK/HlJ mice are more prone to diabetic nephropathy, whereas the most widely used C57BL/6J mice are relatively resistant to development of diabetic nephropathy. ACR, albumin-to-creatinine ratio FITC, fluorescein isothiocyanate GBM, glomerular basement membrane GFR, glomerular filtration rate STZ, streptozotocin UAE, urinary albumin excretion rate Footnotes Accepted June 6, 2005. Received January 24, 2005. DIABETES