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Knockout of the TauT gene predisposes C57BL/6 mice to streptozotocin-induced diabetic nephropathy.

Han X, Patters AB, Ito T, Azuma J, Schaffer SW, Chesney RW - PLoS ONE (2015)

Bottom Line: In this study, we hypothesize that taurine insufficiency is a critical risk factor for development of diabetic nephropathy associated with diabetes mellitus.These animals developed histological changes characteristic of human diabetic nephropathy that included glomerulosclerosis, nodular lesions, arteriosclerosis, arteriolar dilation, and tubulointerstitial fibrosis.Immunohistochemical staining of molecular markers of smooth muscle actin, CD34, Ki67 and collagen IV further confirmed these observations.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Tennessee Health Science Center, and the Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, TN, United States of America.

ABSTRACT
Diabetic nephropathy is the leading cause of end stage renal disease in the world. Although tremendous efforts have been made, scientists have yet to identify an ideal animal model that can reproduce the characteristics of human diabetic nephropathy. In this study, we hypothesize that taurine insufficiency is a critical risk factor for development of diabetic nephropathy associated with diabetes mellitus. This hypothesis was tested in vivo in TauT heterozygous (TauT+/-) and homozygous (TauT-/-) knockout in C57BL/6 background mice. We have shown that alteration of the TauT gene (also known as SLC6A6) has a substantial effect on the susceptibility to development of extensive diabetic kidney disease in both TauT+/- and TauT-/-mouse models of diabetes. These animals developed histological changes characteristic of human diabetic nephropathy that included glomerulosclerosis, nodular lesions, arteriosclerosis, arteriolar dilation, and tubulointerstitial fibrosis. Immunohistochemical staining of molecular markers of smooth muscle actin, CD34, Ki67 and collagen IV further confirmed these observations. Our results demonstrated that both homozygous and heterozygous TauT gene deletion predispose C57BL/6 mice to develop end-stage diabetic kidney disease, which closely replicates the pathological features of diabetic nephropathy in human diabetic patients.

No MeSH data available.


Related in: MedlinePlus

Histologic renal lesions in diabetic TauT-deficient mice.A) Immunohistochemical analysis showing deposition of collagen IV in diabetic TauT+/- and TauT-/- mice at 5 months of DM; B) Immunohistochemistry for CD34 and Ki67 (brown color) in diabetic TauT+/- and TauT-/- mice at 5 months of DM; C) Quantitation of CD34- and Ki67-positive cells. *p < 0.05 vs controls, **p < 0.01 vs controls. Magnification: x400.
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pone.0117718.g005: Histologic renal lesions in diabetic TauT-deficient mice.A) Immunohistochemical analysis showing deposition of collagen IV in diabetic TauT+/- and TauT-/- mice at 5 months of DM; B) Immunohistochemistry for CD34 and Ki67 (brown color) in diabetic TauT+/- and TauT-/- mice at 5 months of DM; C) Quantitation of CD34- and Ki67-positive cells. *p < 0.05 vs controls, **p < 0.01 vs controls. Magnification: x400.

Mentions: The most marked changes in the diabetic TauT-deficient mice were the increased thickness and dilation of both afferent and efferent arterioles of the glomeruli. These features closely replicate the changes in arterioles observed in advanced renal disease associated with human diabetic nephropathy. Immunohistochemical staining for smooth muscle actin (SMA) showed that the arterioles were significantly thickened and dilated in TauT+/- and TauT-/- diabetic mice at 5 months compared to the controls and WT diabetic mice (Fig. 4A and B). These pathological changes were often associated with glomerular necrosis. Although wild-type diabetic mice also demonstrated some glomerular changes, there was no clear damage to the glomerular structure. Immunohistochemical staining demonstrated that collagen IV was heavily deposited in the juxtaglomerular area in TauT-deficient diabetic mice and was associated with mesangial expansion (Fig. 5A).


Knockout of the TauT gene predisposes C57BL/6 mice to streptozotocin-induced diabetic nephropathy.

Han X, Patters AB, Ito T, Azuma J, Schaffer SW, Chesney RW - PLoS ONE (2015)

Histologic renal lesions in diabetic TauT-deficient mice.A) Immunohistochemical analysis showing deposition of collagen IV in diabetic TauT+/- and TauT-/- mice at 5 months of DM; B) Immunohistochemistry for CD34 and Ki67 (brown color) in diabetic TauT+/- and TauT-/- mice at 5 months of DM; C) Quantitation of CD34- and Ki67-positive cells. *p < 0.05 vs controls, **p < 0.01 vs controls. Magnification: x400.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4309680&req=5

pone.0117718.g005: Histologic renal lesions in diabetic TauT-deficient mice.A) Immunohistochemical analysis showing deposition of collagen IV in diabetic TauT+/- and TauT-/- mice at 5 months of DM; B) Immunohistochemistry for CD34 and Ki67 (brown color) in diabetic TauT+/- and TauT-/- mice at 5 months of DM; C) Quantitation of CD34- and Ki67-positive cells. *p < 0.05 vs controls, **p < 0.01 vs controls. Magnification: x400.
Mentions: The most marked changes in the diabetic TauT-deficient mice were the increased thickness and dilation of both afferent and efferent arterioles of the glomeruli. These features closely replicate the changes in arterioles observed in advanced renal disease associated with human diabetic nephropathy. Immunohistochemical staining for smooth muscle actin (SMA) showed that the arterioles were significantly thickened and dilated in TauT+/- and TauT-/- diabetic mice at 5 months compared to the controls and WT diabetic mice (Fig. 4A and B). These pathological changes were often associated with glomerular necrosis. Although wild-type diabetic mice also demonstrated some glomerular changes, there was no clear damage to the glomerular structure. Immunohistochemical staining demonstrated that collagen IV was heavily deposited in the juxtaglomerular area in TauT-deficient diabetic mice and was associated with mesangial expansion (Fig. 5A).

Bottom Line: In this study, we hypothesize that taurine insufficiency is a critical risk factor for development of diabetic nephropathy associated with diabetes mellitus.These animals developed histological changes characteristic of human diabetic nephropathy that included glomerulosclerosis, nodular lesions, arteriosclerosis, arteriolar dilation, and tubulointerstitial fibrosis.Immunohistochemical staining of molecular markers of smooth muscle actin, CD34, Ki67 and collagen IV further confirmed these observations.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Tennessee Health Science Center, and the Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, TN, United States of America.

ABSTRACT
Diabetic nephropathy is the leading cause of end stage renal disease in the world. Although tremendous efforts have been made, scientists have yet to identify an ideal animal model that can reproduce the characteristics of human diabetic nephropathy. In this study, we hypothesize that taurine insufficiency is a critical risk factor for development of diabetic nephropathy associated with diabetes mellitus. This hypothesis was tested in vivo in TauT heterozygous (TauT+/-) and homozygous (TauT-/-) knockout in C57BL/6 background mice. We have shown that alteration of the TauT gene (also known as SLC6A6) has a substantial effect on the susceptibility to development of extensive diabetic kidney disease in both TauT+/- and TauT-/-mouse models of diabetes. These animals developed histological changes characteristic of human diabetic nephropathy that included glomerulosclerosis, nodular lesions, arteriosclerosis, arteriolar dilation, and tubulointerstitial fibrosis. Immunohistochemical staining of molecular markers of smooth muscle actin, CD34, Ki67 and collagen IV further confirmed these observations. Our results demonstrated that both homozygous and heterozygous TauT gene deletion predispose C57BL/6 mice to develop end-stage diabetic kidney disease, which closely replicates the pathological features of diabetic nephropathy in human diabetic patients.

No MeSH data available.


Related in: MedlinePlus