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

Lee,Mi  Hee; Choi,Eun  Nam; Jeon,Yeo  Jin; Jung,Sung-Chul

doi:10.3892/ijmm.2012.1139

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

Authors:
- Mi Hee Lee
- Eun Nam Choi
- Yeo Jin Jeon
- Sung-Chul Jung
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Affiliations: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea
Published online on: September 24, 2012 https://doi.org/10.3892/ijmm.2012.1139
Pages: 1275-1280
Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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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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