Epithelial-Mesenchymal Transition in Kidney Tubular Epithelial Cells Induced by Globotriaosylsphingosine and Globotriaosylceramide

• Published in: PloS one 2015-08, Vol.10 (8), p.e0136442-e0136442
• Main Authors: Jeon, Yeo Jin, Jung, Namhee, Park, Joo-Won, Park, Hae-Young, Jung, Sung-Chul
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; a-Galactosidase; AKT protein; Animals; Biochemistry; Biopsy; Biotechnology; Cardiovascular diseases; Care and treatment; Cell Line; Complications and side effects; E-cadherin; Endothelium; Enzymes; Epithelial cells; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - physiology; Fabry's disease; Fibroblasts; Fibrosis; Fluorescent Antibody Technique; Galactosidase; Globotriaosylceramide; Glycolipids - pharmacology; Growth factors; Humans; Hypoxia; Kidney Tubules, Proximal - cytology; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - physiology; Kidneys; Kinases; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Markers; Medical diagnosis; Medical treatment; Medicine; Mesangial Cells - cytology; Mesangial Cells - drug effects; Mesangial Cells - physiology; Mesenchyme; Mice; N-Cadherin; Patients; Phenotypes; Phosphorylation; Polyclonal antibodies; Risk factors; Rodents; Smooth muscle; Sphingolipids - pharmacology; Stem cell research; Trihexosylceramides - pharmacology; Urothelium - cytology; Urothelium - drug effects; Urothelium - physiology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0136442

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.