Influence of genetic background on albuminuria and kidney injury in Ins2(+/C96Y)
(Akita) mice.
Authors Gurley SB, Mach CL, Stegbauer J, Yang J, Snow KP, Hu A, Meyer TW, Coffman TM
Submitted By Thomas Coffman on 3/24/2010
Status Published
Journal American journal of physiology. Renal physiology
Year 2010
Date Published 3/1/2010
Volume : Pages 298(3) : F788 - F795
PubMed Reference 20042456
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.

Investigators with authorship
Thomas CoffmanDuke University Medical Center


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