Integrin α1/Akita double-knockout mice on a Balb/c background develop advanced features of human diabetic nephropathy.
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 α1KO 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 α1KOAkitaKO mice at 6 months of age. Thus, the integrin α1KOAkitaKO Balb/c mouse represents a promising model presenting with most features of human diabetic nephropathy.
Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
Ling
L
Yu
Yan
Y
Su
Paisit
P
Paueksakon
Huifang
H
Cheng
Xiwu
X
Chen
Hongtao
H
Wang
Raymond C
RC
Harris
Roy
R
Zent
Ambra
A
Pozzi
D000367:Age Factors; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D005919:Glomerular Filtration Rate; D005921:Glomerulonephritis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000235:genetics*; D039423:Integrin alpha1 / Q000235:genetics* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D010641:Phenotype; D012598:Sclerosis; D012720:Severity of Illness Index
D001786:Blood Glucose; C561967:Ins2 protein, mouse; D007328:Insulin; D039423:Integrin alpha1