Integrin a1/Akita double-knockout mice on a Balb/c background develop advanced
features of human diabetic nephropathy.
Authors Yu L, Su Y, Paueksakon P, Cheng H, Chen X, Wang H, Harris RC, Zent R, Pozzi A
Submitted By Raymond Harris on 2/22/2012
Status Published
Journal Kidney international
Year 2012
Date Published 6/1/2012
Volume : Pages 81 : 1086 - 1097
PubMed Reference 22297672
Abstract Animal models that mimic human diabetic nephropathy are useful to identify key
factors in pathogenesis of this disease, as well as the development of new
therapies. Several mouse models of diabetes have features of human diabetic
nephropathy, yet none of these completely fulfill the Animal Models of Diabetes
Complications Consortium criteria and completely reproduce pathological and
functional features of the human disease. The Akita mouse carries a mutation in
the insulin-2 gene and, to date, only survives as heterozygotes that develop
spontaneous type 1 diabetes. Here we show that Akita mice with mutation of both
insulin-2 alleles (Akita knockout (KO)) survive if crossed onto the Balb/c
background. These mice develop hyperglycemia, more severe albuminuria, and
mesangial sclerosis compared with heterozygous mice on the same genetic
background. Interestingly, crossing these AkitaKO mice with integrin a1KO mice,
a model of exacerbated glomerulosclerosis after injury and also on the Balb/c
background, resulted in a 16-fold increase in albuminuria, significant mesangial
matrix expansion, nodular and diffuse glomerulosclerosis, and a 2-fold increase
in glomerular basement membrane thickening when compared with nondiabetic mice.
Moreover, a significant decline in glomerular filtration was evident in the
a1KOAkitaKO mice at 6 months of age. Thus, the integrin a1KOAkitaKO Balb/c mouse
represents a promising model presenting with most features of human diabetic

Investigators with authorship
Raymond HarrisVanderbilt University