title: Influence of genetic background on albuminuria and kidney injury in Ins2(+/C96Y) (Akita) mice.
abstract: Previous studies have shown that Akita mice bearing the Ins2(+/C96Y) mutation have significant advantages as a type I diabetes platform for developing models of diabetic nephropathy (DN; Gurley SB, Clare SE, Snow KP, Hu A, Meyer TW, Coffman TM. Am J Physiol Renal Physiol 290: F214-F222, 2006). In view of the critical role for genetic factors in determining susceptibility to DN in humans, we investigated the role of genetic background on kidney injury in Akita mice. To generate a series of inbred Akita mouse lines, we back-crossed the Ins2(C96Y) mutation more than six generations onto the 129/SvEv and DBA/2 backgrounds and compared the extent of hyperglycemia and renal disease with the standard C57BL/6-Ins2(+/C96Y) line. Male mice from all three Akita strains developed marked and equivalent hyperglycemia. However, there were significant differences in the level of albuminuria among the lines with a hierarchy of DBA/2 > 129/SvEv > C57BL/6. Renal and glomerular hypertrophy was seen in all of the lines, but significant increases in mesangial matrix compared with baseline nondiabetic controls were observed only in the 129 and C57BL/6 backgrounds. In F1(DBA/2 x C57BL/6)-Ins2(+/C96Y) mice, the extent of albuminuria was similar to the parental DBA/2-Ins2(+/C96Y) line; they also developed marked hyperfiltration. These studies identify strong effects of genetic background to modify the renal phenotype associated with the Ins2(C96Y) mutation. Identification of these naturally occurring strain differences should prove useful for nephropathy modeling and may be exploited to allow identification of novel susceptibility alleles for albuminuria in diabetes.
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, North Carolina, USA. susan.gurley@duke.edu
authors.forename: Susan B
authors.initials: SB
authors.lastname: Gurley
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Mach
authors.forename: Johannes
authors.initials: J
authors.lastname: Stegbauer
authors.forename: Jihong
authors.initials: J
authors.lastname: Yang
authors.forename: Kamie P
authors.initials: KP
authors.lastname: Snow
authors.forename: Ann
authors.initials: A
authors.lastname: Hu
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Meyer
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coffman
mesh_terms: D000367:Age Factors; D000419:Albuminuria / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001786:Blood Glucose / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D005919:Glomerular Filtration Rate / Q000235:genetics; D006943:Hyperglycemia / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006984:Hypertrophy; D007328:Insulin / Q000235:genetics*; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D009154:Mutation; D009929:Organ Size; D010641:Phenotype; D013045:Species Specificity
chemical_list: D001786:Blood Glucose; D007328:Insulin