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Possible role of transforming growth factor-β1 and vascular endothelial growth factor in Fabry disease nephropathy.

Lee MH, Choi EN, Jeon YJ, Jung SC - Int. J. Mol. Med. (2012)

Bottom Line: We found that the protein expression levels of renal thrombospondin-1 (TSP-1), TGF-β1 and VEGF were higher in the kidneys from Fabry mice compared to wild-type mice.The expression levels of VEGF receptor 2 (VEGFR2), fibroblast growth factor-2 (FGF-2) and phospho-p38 (P-p38) were also higher in the kidneys from Fabry mice compared with wild-type mice.To test whether Gb3 accumulation can induce apoptosis, we incubated bovine aortic endothelial cells with Gb3 and found increased expression of TGF-β1, VEGFR2, VEGF, FGF-2 and P-p38.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea.

ABSTRACT
Fabry disease is a lysosomal storage disorder (LSD) caused by deficiency of α-galactosidase A (α-gal A), resulting in deposition of globotriaosylceramide (Gb3; also known as ceramide trihexoside) in the vascular endothelium of many organs. A gradual accumulation of Gb3 leads to cardiovascular, cerebrovascular and renal dysfunction. Endothelial cell dysfunction leads to renal complications, one of the main symptoms of Fabry disease. However, the pathological mechanisms by which endothelial dysfunction occurs in Fabry disease are poorly characterized. The purpose of this study was to investigate whether the expression of transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF) is associated with the renal pathogenesis of Fabry disease. We found that the protein expression levels of renal thrombospondin-1 (TSP-1), TGF-β1 and VEGF were higher in the kidneys from Fabry mice compared to wild-type mice. The expression levels of VEGF receptor 2 (VEGFR2), fibroblast growth factor-2 (FGF-2) and phospho-p38 (P-p38) were also higher in the kidneys from Fabry mice compared with wild-type mice. Activities of cysteine aspartic acid protease (caspase)-6 and caspase-9 were higher in kidneys from Fabry than from the wild-type mice. These results suggest that overexpression of TGF-β1 and VEGF in the Fabry mouse kidney might contribute to Fabry disease nephropathy by inducing apoptosis. To test whether Gb3 accumulation can induce apoptosis, we incubated bovine aortic endothelial cells with Gb3 and found increased expression of TGF-β1, VEGFR2, VEGF, FGF-2 and P-p38. The combination of increased expression of TGF-β1 and VEGF caused by Gb3 accumulation may allow upregulation of FGF-2, VEGFR2 and P-p38 expression, and these changes may be associated with Fabry disease nephropathy by inducing apoptosis.

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Protein expression levels of TSP-1, VEGF and TGF-β1 in the Fabry mouse kidney.(A) Results of western blot analysis using the antibodies described in Materials andmethods. (B) Expression level of each protein was normalized to the internal controlβ-actin and represented as the expression ratio relative to that in wild-typemice. The values are expressed as the mean ± SD (n=3).*P<0.05 and **P<0.01,wild-type vs. Fabry mice.
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f1-ijmm-30-06-1275: Protein expression levels of TSP-1, VEGF and TGF-β1 in the Fabry mouse kidney.(A) Results of western blot analysis using the antibodies described in Materials andmethods. (B) Expression level of each protein was normalized to the internal controlβ-actin and represented as the expression ratio relative to that in wild-typemice. The values are expressed as the mean ± SD (n=3).*P<0.05 and **P<0.01,wild-type vs. Fabry mice.

Mentions: The expression patterns of TSP-1, VEGF and TGF-β1 proteins were examined in thekidneys from Fabry and wild-type mice. As expected, TSP-1 protein expression was234% higher in Fabry than in wild-type mice (Fig. 1) (P<0.05). VEGF protein expression was 214%higher in Fabry mice (P<0.05). TGF-β1 protein expression was 422%higher in Fabry than in wild-type mice (P<0.01). These results suggest that VEGFexpression is influenced through another pathway associated with TGF-β1.


Possible role of transforming growth factor-β1 and vascular endothelial growth factor in Fabry disease nephropathy.

Lee MH, Choi EN, Jeon YJ, Jung SC - Int. J. Mol. Med. (2012)

Protein expression levels of TSP-1, VEGF and TGF-β1 in the Fabry mouse kidney.(A) Results of western blot analysis using the antibodies described in Materials andmethods. (B) Expression level of each protein was normalized to the internal controlβ-actin and represented as the expression ratio relative to that in wild-typemice. The values are expressed as the mean ± SD (n=3).*P<0.05 and **P<0.01,wild-type vs. Fabry mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042857&req=5

f1-ijmm-30-06-1275: Protein expression levels of TSP-1, VEGF and TGF-β1 in the Fabry mouse kidney.(A) Results of western blot analysis using the antibodies described in Materials andmethods. (B) Expression level of each protein was normalized to the internal controlβ-actin and represented as the expression ratio relative to that in wild-typemice. The values are expressed as the mean ± SD (n=3).*P<0.05 and **P<0.01,wild-type vs. Fabry mice.
Mentions: The expression patterns of TSP-1, VEGF and TGF-β1 proteins were examined in thekidneys from Fabry and wild-type mice. As expected, TSP-1 protein expression was234% higher in Fabry than in wild-type mice (Fig. 1) (P<0.05). VEGF protein expression was 214%higher in Fabry mice (P<0.05). TGF-β1 protein expression was 422%higher in Fabry than in wild-type mice (P<0.01). These results suggest that VEGFexpression is influenced through another pathway associated with TGF-β1.

Bottom Line: We found that the protein expression levels of renal thrombospondin-1 (TSP-1), TGF-β1 and VEGF were higher in the kidneys from Fabry mice compared to wild-type mice.The expression levels of VEGF receptor 2 (VEGFR2), fibroblast growth factor-2 (FGF-2) and phospho-p38 (P-p38) were also higher in the kidneys from Fabry mice compared with wild-type mice.To test whether Gb3 accumulation can induce apoptosis, we incubated bovine aortic endothelial cells with Gb3 and found increased expression of TGF-β1, VEGFR2, VEGF, FGF-2 and P-p38.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea.

ABSTRACT
Fabry disease is a lysosomal storage disorder (LSD) caused by deficiency of α-galactosidase A (α-gal A), resulting in deposition of globotriaosylceramide (Gb3; also known as ceramide trihexoside) in the vascular endothelium of many organs. A gradual accumulation of Gb3 leads to cardiovascular, cerebrovascular and renal dysfunction. Endothelial cell dysfunction leads to renal complications, one of the main symptoms of Fabry disease. However, the pathological mechanisms by which endothelial dysfunction occurs in Fabry disease are poorly characterized. The purpose of this study was to investigate whether the expression of transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF) is associated with the renal pathogenesis of Fabry disease. We found that the protein expression levels of renal thrombospondin-1 (TSP-1), TGF-β1 and VEGF were higher in the kidneys from Fabry mice compared to wild-type mice. The expression levels of VEGF receptor 2 (VEGFR2), fibroblast growth factor-2 (FGF-2) and phospho-p38 (P-p38) were also higher in the kidneys from Fabry mice compared with wild-type mice. Activities of cysteine aspartic acid protease (caspase)-6 and caspase-9 were higher in kidneys from Fabry than from the wild-type mice. These results suggest that overexpression of TGF-β1 and VEGF in the Fabry mouse kidney might contribute to Fabry disease nephropathy by inducing apoptosis. To test whether Gb3 accumulation can induce apoptosis, we incubated bovine aortic endothelial cells with Gb3 and found increased expression of TGF-β1, VEGFR2, VEGF, FGF-2 and P-p38. The combination of increased expression of TGF-β1 and VEGF caused by Gb3 accumulation may allow upregulation of FGF-2, VEGFR2 and P-p38 expression, and these changes may be associated with Fabry disease nephropathy by inducing apoptosis.

Show MeSH
Related in: MedlinePlus