Fabry disease is a lysosomal storage disorder caused by deficiency of
alpha-galactosidase A (α-gal A), which results in the deposition of
globotriaosylceramide (Gb3) in the vascular endothelium. Globotriaosylsphingosine (lyso-Gb3), a deacylated Gb3, is also increased in the plasma of patients with
Fabry disease. Renal
fibrosis is a key feature of advanced
Fabry disease patients. Therefore, we evaluated the association of Gb3 and
lyso-Gb3 accumulation and the epithelial-mesenchymal transition (EMT) on tubular epithelial cells of the kidney. In HK2 cells, exogenous treatments of Gb3 and
lyso-Gb3 increased the expression of TGF-β, EMT markers (
N-cadherin and α-SMA), and phosphorylation of PI3K/AKT, and decreased the expression of
E-cadherin.
Lyso-Gb3, rather than Gb3, strongly induced EMT in HK2 cells. In the mouse renal mesangial cell line, SV40 MES 13 cells, Gb3 strongly induced phenotype changes. The EMT induced by Gb3 was inhibited by
enzyme α-gal A treatment, but EMT induced by
lyso-Gb3 was not abrogated by
enzyme treatment. However, TGF-β receptor inhibitor (TRI,
SB525334) inhibited the activation of TGF-β and EMT markers in HK2 cells with Gb3 and
lyso-Gb3 treatments. This study suggested that increased plasma
lyso-Gb3 has a crucial role in the development of renal
fibrosis through the cell-specific induction of the EMT in
Fabry disease, and that TRI treatment, alongside
enzyme replacement therapy, could be a potential therapeutic option for patients with
Fabry disease.