title: Possible role of transforming growth factor-β1 and vascular endothelial             growth factor in Fabry disease nephropathy.
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.
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University,                     Seoul 158-710, Republic of Korea.
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Lee
authors.forename: Eun Nam
authors.initials: EN
authors.lastname: Choi
authors.forename: Yeo Jin
authors.initials: YJ
authors.lastname: Jeon
authors.forename: Sung-Chul
authors.initials: SC
authors.lastname: Jung
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D000795:Fabry Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D019700:Thrombospondin 1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014281:Trihexosylceramides / Q000502:physiology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; D014281:Trihexosylceramides; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2; C018549:globotriaosylceramide; D040301:Vascular Endothelial Growth Factor Receptor-2; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases