Limits...
Integrin α1/Akita double-knockout mice on a Balb/c background develop advanced features of human diabetic nephropathy.

Yu L, Su Y, Paueksakon P, Cheng H, Chen X, Wang H, Harris RC, Zent R, Pozzi A - Kidney Int. (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.

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 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.

Show MeSH

Related in: MedlinePlus

Decreased glomerular capillary loops in α1KOAkitaKO Balb/c mice(A) CD31 staining of kidney sections from 6 months old wild type (WT), AkitaKO and α1KOAkitaKO mice. The glomerular area is marked by dotted lines. (B) The degree of vascularization per glomerulus was quantified using Scion Image as described in Materials and Methods. Data represent the mean +/− SD of 20 glomeruli (5 glomeruli/mouse with 4 mice analyzed). * and # are as in Figure 3.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3345314&req=5

Figure 8: Decreased glomerular capillary loops in α1KOAkitaKO Balb/c mice(A) CD31 staining of kidney sections from 6 months old wild type (WT), AkitaKO and α1KOAkitaKO mice. The glomerular area is marked by dotted lines. (B) The degree of vascularization per glomerulus was quantified using Scion Image as described in Materials and Methods. Data represent the mean +/− SD of 20 glomeruli (5 glomeruli/mouse with 4 mice analyzed). * and # are as in Figure 3.

Mentions: One of the features of the glomerular lesions of diabetic nephropathy is collapse of the glomerular tufts due to scar tissue consisting of ECM 19. To define the area occupied by the glomerular capillaries, we stained kidney frozen sections of 6 months old non-diabetic and diabetic mice with CD31, a well-defined marker of blood vessels. Compared to non-diabetic mice, there were significantly decreased CD31 positive structures in the glomeruli of both AkitaKO and α1KOAkitaKO mice and this reduction was much more evident in the latter group (Fig. 8).


Integrin α1/Akita double-knockout mice on a Balb/c background develop advanced features of human diabetic nephropathy.

Yu L, Su Y, Paueksakon P, Cheng H, Chen X, Wang H, Harris RC, Zent R, Pozzi A - Kidney Int. (2012)

Decreased glomerular capillary loops in α1KOAkitaKO Balb/c mice(A) CD31 staining of kidney sections from 6 months old wild type (WT), AkitaKO and α1KOAkitaKO mice. The glomerular area is marked by dotted lines. (B) The degree of vascularization per glomerulus was quantified using Scion Image as described in Materials and Methods. Data represent the mean +/− SD of 20 glomeruli (5 glomeruli/mouse with 4 mice analyzed). * and # are as in Figure 3.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3345314&req=5

Figure 8: Decreased glomerular capillary loops in α1KOAkitaKO Balb/c mice(A) CD31 staining of kidney sections from 6 months old wild type (WT), AkitaKO and α1KOAkitaKO mice. The glomerular area is marked by dotted lines. (B) The degree of vascularization per glomerulus was quantified using Scion Image as described in Materials and Methods. Data represent the mean +/− SD of 20 glomeruli (5 glomeruli/mouse with 4 mice analyzed). * and # are as in Figure 3.
Mentions: One of the features of the glomerular lesions of diabetic nephropathy is collapse of the glomerular tufts due to scar tissue consisting of ECM 19. To define the area occupied by the glomerular capillaries, we stained kidney frozen sections of 6 months old non-diabetic and diabetic mice with CD31, a well-defined marker of blood vessels. Compared to non-diabetic mice, there were significantly decreased CD31 positive structures in the glomeruli of both AkitaKO and α1KOAkitaKO mice and this reduction was much more evident in the latter group (Fig. 8).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.

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 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.

Show MeSH
Related in: MedlinePlus