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

Abstract

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.

Formin-dependent TGF-β signaling for epithelial to mesenchymal transition

“…, 2001 ; Lamouille and Derynck, 2007 ; Haynes et al. , 2011 ), and HK2 human kidney epithelial cells ( Jeon et al. , 2015 ; Rana et al.…”

High Lyso-Gb3 Plasma Levels Associated with Decreased miR-29 and miR-200 Urinary Excretion in Young Non-Albuminuric Male Patient with Classic Fabry Disease

“…The origin of excessive plasma accumulation of Lyso-Gb3 in affected patients is not clearly identified. It has been proposed that it comes from the deacylation of abnormally accumulated Gb3 molecules due to the deficit of α GalA [9, 10, 14]. Elevated plasma Lyso-Gb3 is a hallmark of classical FD in males although in Fabry females it is relatively lower [15].…”

“…Gb3 and lyso-Gb3 are involved with various cellular mechanisms implying renal fibrosis [9, 10]. Glycolipids, mainly Gb3 are deposited in all types of kidney cells [5, 6].…”

“…The highest Lyso-Gb3 plasma concentrations have been observed in males affected by most severe FD form (“Classic” or “Type I” FD) [8]. The Lyso-Gb3 deleterious effects on podocytes and renal tubular cells have been demonstrated in both animal and human models of Fabry nephropathy [9, 10]. In podocytes, exposure to Lyso-Gb is correlated with increased Transforming Growth Factor- β eta (TGF- β ) and extracellular matrix components expression, both mechanisms associated with renal fibrosis development [9].…”

“…In podocytes, exposure to Lyso-Gb is correlated with increased Transforming Growth Factor- β eta (TGF- β ) and extracellular matrix components expression, both mechanisms associated with renal fibrosis development [9]. In renal tubular cells exposed to Lyso-Gb3, epithelial-mesenchymal transition has been described as another mechanism related to renal fibrosis [10].…”