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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.

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Histopathology of kidneys from α1KOAkitaKO Balb/c mice(A, C) Representative light micrographs of Periodic Acid Shiff-stained kidney sections from WT, integrin α1KO, AkitaKO and α1KOAkitaKO mice at 4 (A) and 6 (C) months of age. Both AkitaKO and α1KOAkitaKO mice developed mesangial matrix expansion at 4 months of age, although it was more severe in the latter group (A). The increased mesangial expansion was worse in the α1KOAkitaKO mice at 6 months of age and there was evidence of nodular glomerulosclerosis (arrow), which was not present in the AkitaKO mice (C). (B, D) Mesangial sclerosis index was evaluated in kidneys from the mice indicated above and the percentage of mesangial matrix occupying the glomerulus scored as described in Figure 1. Data are presented as the mean +/− SD of 120 glomeruli (30 glomeruli/mouse with a total of 4 mice evaluated). Although both AkitaKO and α1KOAkitaKO mice developed glomerular injury at 4 and 6 months of age, the degree of injury was significantly higher in the latter group. *, **, and # are as in Figure 3.
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Figure 4: Histopathology of kidneys from α1KOAkitaKO Balb/c mice(A, C) Representative light micrographs of Periodic Acid Shiff-stained kidney sections from WT, integrin α1KO, AkitaKO and α1KOAkitaKO mice at 4 (A) and 6 (C) months of age. Both AkitaKO and α1KOAkitaKO mice developed mesangial matrix expansion at 4 months of age, although it was more severe in the latter group (A). The increased mesangial expansion was worse in the α1KOAkitaKO mice at 6 months of age and there was evidence of nodular glomerulosclerosis (arrow), which was not present in the AkitaKO mice (C). (B, D) Mesangial sclerosis index was evaluated in kidneys from the mice indicated above and the percentage of mesangial matrix occupying the glomerulus scored as described in Figure 1. Data are presented as the mean +/− SD of 120 glomeruli (30 glomeruli/mouse with a total of 4 mice evaluated). Although both AkitaKO and α1KOAkitaKO mice developed glomerular injury at 4 and 6 months of age, the degree of injury was significantly higher in the latter group. *, **, and # are as in Figure 3.

Mentions: We next defined the histopathological features of the kidneys of the α1KOAkitaKO mice at 4 and 6 months in order to define the severity of disease in these mice. There was significantly increased mesangial matrix expansion (Figs. 4A and 4C) and glomerulosclerosis score (Figs. 4B and 4D) in the α1KOAkitaKO when compared to the AkitaKO mice at both 4 and 6 months. Due to the severity of the glomerular injury in these mice we carefully defined the histological lesions found within the glomeruli of the α1KOAkitaKO mice. As shown in Figure 5, there was evidence of diffuse and nodular mesangial sclerosis as well as mesangiolysis seen under light microscopy. The mesangial expansion was confirmed on electron microscopy in both the AkitaKO and α1KOAkitaKO mice at 6 months; however it was much more severe in the latter group (Fig. 6A). Furthermore, there was GBM thickening in both genotypes compared to non-diabetic controls, which was significantly more severe in the α1KOAkitaKO mice (Figs. 6A and 6B). Collagen IV is the most abundant extracellular matrix (ECM) component in the glomerulus, and its upregulation has been described in many glomerular diseases, including DN 16. Analysis of 6 months old mice revealed increased glomerular collagen IV deposition in both AkitaKO and α1KOAkitaKO mice compared to non-diabetic mice, although it was more abundant in the latter group (Fig. 7A and 7B). Furthermore, excessive fibrillar collagen deposition in the α1KOAkitaKO mice was confirmed by trichrome staining in both diffuse and nodular mesangial lesions (Fig. 7C).


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)

Histopathology of kidneys from α1KOAkitaKO Balb/c mice(A, C) Representative light micrographs of Periodic Acid Shiff-stained kidney sections from WT, integrin α1KO, AkitaKO and α1KOAkitaKO mice at 4 (A) and 6 (C) months of age. Both AkitaKO and α1KOAkitaKO mice developed mesangial matrix expansion at 4 months of age, although it was more severe in the latter group (A). The increased mesangial expansion was worse in the α1KOAkitaKO mice at 6 months of age and there was evidence of nodular glomerulosclerosis (arrow), which was not present in the AkitaKO mice (C). (B, D) Mesangial sclerosis index was evaluated in kidneys from the mice indicated above and the percentage of mesangial matrix occupying the glomerulus scored as described in Figure 1. Data are presented as the mean +/− SD of 120 glomeruli (30 glomeruli/mouse with a total of 4 mice evaluated). Although both AkitaKO and α1KOAkitaKO mice developed glomerular injury at 4 and 6 months of age, the degree of injury was significantly higher in the latter group. *, **, and # are as in Figure 3.
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Related In: Results  -  Collection

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Figure 4: Histopathology of kidneys from α1KOAkitaKO Balb/c mice(A, C) Representative light micrographs of Periodic Acid Shiff-stained kidney sections from WT, integrin α1KO, AkitaKO and α1KOAkitaKO mice at 4 (A) and 6 (C) months of age. Both AkitaKO and α1KOAkitaKO mice developed mesangial matrix expansion at 4 months of age, although it was more severe in the latter group (A). The increased mesangial expansion was worse in the α1KOAkitaKO mice at 6 months of age and there was evidence of nodular glomerulosclerosis (arrow), which was not present in the AkitaKO mice (C). (B, D) Mesangial sclerosis index was evaluated in kidneys from the mice indicated above and the percentage of mesangial matrix occupying the glomerulus scored as described in Figure 1. Data are presented as the mean +/− SD of 120 glomeruli (30 glomeruli/mouse with a total of 4 mice evaluated). Although both AkitaKO and α1KOAkitaKO mice developed glomerular injury at 4 and 6 months of age, the degree of injury was significantly higher in the latter group. *, **, and # are as in Figure 3.
Mentions: We next defined the histopathological features of the kidneys of the α1KOAkitaKO mice at 4 and 6 months in order to define the severity of disease in these mice. There was significantly increased mesangial matrix expansion (Figs. 4A and 4C) and glomerulosclerosis score (Figs. 4B and 4D) in the α1KOAkitaKO when compared to the AkitaKO mice at both 4 and 6 months. Due to the severity of the glomerular injury in these mice we carefully defined the histological lesions found within the glomeruli of the α1KOAkitaKO mice. As shown in Figure 5, there was evidence of diffuse and nodular mesangial sclerosis as well as mesangiolysis seen under light microscopy. The mesangial expansion was confirmed on electron microscopy in both the AkitaKO and α1KOAkitaKO mice at 6 months; however it was much more severe in the latter group (Fig. 6A). Furthermore, there was GBM thickening in both genotypes compared to non-diabetic controls, which was significantly more severe in the α1KOAkitaKO mice (Figs. 6A and 6B). Collagen IV is the most abundant extracellular matrix (ECM) component in the glomerulus, and its upregulation has been described in many glomerular diseases, including DN 16. Analysis of 6 months old mice revealed increased glomerular collagen IV deposition in both AkitaKO and α1KOAkitaKO mice compared to non-diabetic mice, although it was more abundant in the latter group (Fig. 7A and 7B). Furthermore, excessive fibrillar collagen deposition in the α1KOAkitaKO mice was confirmed by trichrome staining in both diffuse and nodular mesangial lesions (Fig. 7C).

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