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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 caspases in Fabry mouse kidney. Proteins from renal tissuewere immunoblotted. (A) Results of western blot analysis using the antibodies describedin Materials and methods. (B) The expression level of each protein was normalized tothat of the internal control β-actin and is represented as the expression ratiorelative to that in wild-type mice. The values are expressed as the mean ± SD(n=3). *P<0.05, wild-type vs. Fabry mice.
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f3-ijmm-30-06-1275: Protein expression levels of caspases in Fabry mouse kidney. Proteins from renal tissuewere immunoblotted. (A) Results of western blot analysis using the antibodies describedin Materials and methods. (B) The expression level of each protein was normalized tothat of the internal control β-actin and is represented as the expression ratiorelative to that in wild-type mice. The values are expressed as the mean ± SD(n=3). *P<0.05, wild-type vs. Fabry mice.

Mentions: The degree of activation of caspase-6, -9 and -12 was determined by measuring the levelsof the cleaved forms of these caspases. The results shown in Fig. 3 indicate that the levels ofcleaved caspase-6 (148%, P<0.05) and cleaved caspase-9 (157%,P<0.05) were significantly higher in Fabry mice than in wild-type mice. Cleavedcaspase-12 level increased nonsignificantly (163%, P=0.06). To confirmthat apoptosis was induced in the kidneys of Fabry mice, caspase-3/7 activity of keyapoptotic proteins was measured using a colorimetric assay. The results shown in Fig. 4 indicate that caspase-3/7 activitywas 128% higher in the kidney lysates from Fabry mice than in those from wild-typemice. In enzyme replacement therapy (ERT)-treated Fabry mice, activity of caspase-3/7 was68% lower than that in the untreated Fabry mice (P<0.01).


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 caspases in Fabry mouse kidney. Proteins from renal tissuewere immunoblotted. (A) Results of western blot analysis using the antibodies describedin Materials and methods. (B) The expression level of each protein was normalized tothat of the internal control β-actin and is represented as the expression ratiorelative to that in wild-type mice. The values are expressed as the mean ± SD(n=3). *P<0.05, wild-type vs. Fabry mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3-ijmm-30-06-1275: Protein expression levels of caspases in Fabry mouse kidney. Proteins from renal tissuewere immunoblotted. (A) Results of western blot analysis using the antibodies describedin Materials and methods. (B) The expression level of each protein was normalized tothat of the internal control β-actin and is represented as the expression ratiorelative to that in wild-type mice. The values are expressed as the mean ± SD(n=3). *P<0.05, wild-type vs. Fabry mice.
Mentions: The degree of activation of caspase-6, -9 and -12 was determined by measuring the levelsof the cleaved forms of these caspases. The results shown in Fig. 3 indicate that the levels ofcleaved caspase-6 (148%, P<0.05) and cleaved caspase-9 (157%,P<0.05) were significantly higher in Fabry mice than in wild-type mice. Cleavedcaspase-12 level increased nonsignificantly (163%, P=0.06). To confirmthat apoptosis was induced in the kidneys of Fabry mice, caspase-3/7 activity of keyapoptotic proteins was measured using a colorimetric assay. The results shown in Fig. 4 indicate that caspase-3/7 activitywas 128% higher in the kidney lysates from Fabry mice than in those from wild-typemice. In enzyme replacement therapy (ERT)-treated Fabry mice, activity of caspase-3/7 was68% lower than that in the untreated Fabry mice (P<0.01).

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