Epithelial-Mesenchymal Transition in Kidney Tubular Epithelial Cells Induced by Globotriaosylsphingosine and Globotriaosylceramide.
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.
Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, South Korea.
Yeo Jin
YJ
Jeon
Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, South Korea.
Namhee
N
Jung
Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, South Korea.
Joo-Won
JW
Park
Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, South Korea.
Hae-Young
HY
Park
Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, South Korea.
Sung-Chul
SC
Jung
D000818:Animals; D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006017:Glycolipids / Q000494:pharmacology*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D013107:Sphingolipids / Q000494:pharmacology*; D014281:Trihexosylceramides / Q000494:pharmacology*; D019459:Urothelium / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D006017:Glycolipids; D013107:Sphingolipids; D014281:Trihexosylceramides; C063288:globotriaosyl lysosphingolipid; C018549:globotriaosylceramide