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A Sensitized Screen of N-ethyl-N-nitrosourea–Mutagenized Mice Identifies Dominant Mutants Predisposed to Diabetic Nephropathy

Elena E. Tchekneva^*, Eugene M. Rinchik, Dina Polosukhina^*, Linda S. Davis^*, Veronika Kadkina^*, Yassir Mohamed^*, Steve R. Dunn, Kumar Sharma, Zhonghua Qi^*, Agnes B. Fogo^*, and Matthew D. Breyer^*,||,¶

^* Division of Nephrology, Department of Medicine, Department of Pathology, and ^|| Department of Molecular Physiology and Biophysics, Vanderbilt University, and ^¶ Veterans Administration Medical Center, Nashville, Tennessee; Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, and Taconic Farms, Inc., Hudson, New York; and Dorrance Hamilton Research Laboratories, Division of Nephrology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania

Address correspondence to: Dr. Elena E. Tchekneva, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, 21st Avenue S. at Garland, Nashville, TN 37232. Phone: 615-343-9867; Fax: 615-343-4704; E-mail: elena.tchekneva{at}vanderbilt.edu

Received for publication February 22, 2006. Accepted for publication October 3, 2006.

Diabetic nephropathy (DN) is a late diabetic complication that comprises progressively increasing albuminuria, declining GFR, and increased cardiovascular risk. Only a minority of patients with diabetes (25 to 40%) develop nephropathy, and there is evidence that heritable genetic factors predispose these "at-risk" individuals to DN. Comparing variability among inbred mouse strains with respect to a specific phenotype can model interhuman variability, and each strain represents a genetically homogeneous system with a defined risk for nephropathy. C57BL/6 mice, which are relatively resistant to DN, were mutagenized using N-ethyl-N-nitrosourea and screened for mutants that developed excess albuminuria on a sensitizing type 1 diabetic background contributed by the dominant Akita mutation in insulin-2 gene (Ins2^Akita). Two of 375 diabetic G1 founders were found to exhibit albumin excretion rates persistently 10-fold greater than albumin excretion rates in nonmutagenized Ins2^Akita controls. This albuminuria trait was heritable and transmitted to approximately 50% of Ins2^Akita G2 and G3 progeny, consistent with a simple, dominantly inherited trait, but was never observed in nondiabetic offspring. During the course of 1 yr, albuminuric Ins2^Akita G2 and G3 progeny developed reduced inulin clearance with elevated blood urea nitrogen and plasma creatinine. Glomerular histology revealed mesangial expansion, and glomerular basement membrane thickening as determined by electron microscopy was enhanced in diabetic mutant kidneys. Hereditary albuminuric N-ethyl-N-nitrosourea–induced mutants were redesignated as Nphrp1 (nephropathy1) and Nphrp2 (nephropathy2) mice for two generated lines. These novel mutants provide new, robust mouse models of DN and should help to elucidate the underlying genetic basis of predisposition to DN.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673