Genetic modulation of diabetic nephropathy among mouse strains with Ins2 Akita
Authors Wu X, Davis RC, McMillen TS, Schaeffer V, Zhou Z, Qi H, Mazandarani PN, Alialy
R, Hudkins KL, Lusis AJ, LeBoeuf RC
Submitted By Submitted Externally on 12/8/2014
Status Published
Journal Physiological reports
Year 2014
Date Published 11/1/2014
Volume : Pages 2 : Not Specified
PubMed Reference 25428948
Abstract Diabetic nephropathy (DN) is a major complication of diabetes and the leading
cause of end-stage renal disease. DN is characterized by changes in kidney
structure and function but the underlying genetic and molecular factors are
poorly understood. We used a mouse diversity panel to explore the genetic basis
of DN traits in mice carrying the Ins2 Akita mutation. Twenty-eight Akita
strains were generated by breeding this panel to DBA/2.Akita mice. Male F1
diabetic and nondiabetic littermates were evaluated for DN-related traits. Urine
albumin-to-creatinine ratios (ACRs), volume and cystatin C as well as blood urea
nitrogen and lipoprotein levels varied significantly among the diabetic strains.
For most Akita strains, ACR values increased 2- to 6-fold over euglycemic
control values. However, six strains exhibited changes in ACR exceeding 10-fold
with two strains (NOD/ShiLt and CBA) showing 50- to 83- fold increases. These
increases are larger than previously reported among available DN mouse models
establishing these strains as useful for additional studies of renal function.
ACRs correlated with cystatin C (P = 0.0286), a measure of hyperfiltration and
an interstitial tubular marker associated with DN onset in humans suggesting
that tubule damage as well as podocyte-stress contributed to reduced kidney
function assessed by ACR. Although large changes were seen for ACRs, severe
nephropathology was absent. However, glomerular hypertrophy and collagen IV
content were found to vary significantly among strains suggesting a genetic
basis for early onset features of DN. Our results define the range of DN
phenotypes that occur among common inbred strains of mice.

Investigators with authorship
Richard DavisUniversity of California Los Angeles