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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 TGF-β1, VEGFR2, VEGF, FGF-2 and P-p38 in BAECs.BAECs were incubated with vehicle, DMSO alone (Cont) or 15 μMGb3 for 2 or 8 h. (A) Results of western blot analysis using the antibodies described inMaterials and methods. (B) The expression level of each protein was normalized to thatof the internal control β-actin and is represented as the expression ratiorelative to that in the control BAECs. The dotted line represents the expression levelsin the control BAECs.
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f5-ijmm-30-06-1275: Protein expression levels of TGF-β1, VEGFR2, VEGF, FGF-2 and P-p38 in BAECs.BAECs were incubated with vehicle, DMSO alone (Cont) or 15 μMGb3 for 2 or 8 h. (A) Results of western blot analysis using the antibodies described inMaterials and methods. (B) The expression level of each protein was normalized to thatof the internal control β-actin and is represented as the expression ratiorelative to that in the control BAECs. The dotted line represents the expression levelsin the control BAECs.

Mentions: To investigate whether Gb3 accumulation induces the expression of TGF-β1 and VEGFin vitro in BAECs in a manner similar to that observed in Fabry mice,BAECs were treated either with control (vehicle, DMSO alone) or 15μM Gb3 for 2 or 8 h (Fig. 5). The protein expression levels of TGF-β1, VEGFR2,VEGF, FGF-2 and P-p38 were higher in Gb3-treated BAECs than in control BAECs. Expressionof these proteins was higher in BAECs treated with Gb3 for 8 h compared with 2 h.


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 TGF-β1, VEGFR2, VEGF, FGF-2 and P-p38 in BAECs.BAECs were incubated with vehicle, DMSO alone (Cont) or 15 μMGb3 for 2 or 8 h. (A) Results of western blot analysis using the antibodies described inMaterials and methods. (B) The expression level of each protein was normalized to thatof the internal control β-actin and is represented as the expression ratiorelative to that in the control BAECs. The dotted line represents the expression levelsin the control BAECs.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5-ijmm-30-06-1275: Protein expression levels of TGF-β1, VEGFR2, VEGF, FGF-2 and P-p38 in BAECs.BAECs were incubated with vehicle, DMSO alone (Cont) or 15 μMGb3 for 2 or 8 h. (A) Results of western blot analysis using the antibodies described inMaterials and methods. (B) The expression level of each protein was normalized to thatof the internal control β-actin and is represented as the expression ratiorelative to that in the control BAECs. The dotted line represents the expression levelsin the control BAECs.
Mentions: To investigate whether Gb3 accumulation induces the expression of TGF-β1 and VEGFin vitro in BAECs in a manner similar to that observed in Fabry mice,BAECs were treated either with control (vehicle, DMSO alone) or 15μM Gb3 for 2 or 8 h (Fig. 5). The protein expression levels of TGF-β1, VEGFR2,VEGF, FGF-2 and P-p38 were higher in Gb3-treated BAECs than in control BAECs. Expressionof these proteins was higher in BAECs treated with Gb3 for 8 h compared with 2 h.

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