Globotriaosylceramide and globotriaosylsphingosine mediated epithelial‐to‐mesenchymal transition in kidney cells: implication for Fabry disease nephropathy (600.1)

Abstract

Fabry disease is a lysosomal storage disorder caused by deficiency of α‐galactosidase A (α‐gal A), resulting in deposition of globotriaosylceramide (Gb3) in the vascular endothelium. Deacylated Gb3, globotriaosylsphingosine (lyso‐Gb3), also accumulated in the tissues of Fabry disease patients. Lyso‐Gb3 has been suggested as a candidate biomarker. According to renal and cardiac pathological findings, epithelial‐to‐mesenchymal transition (EMT) could be a possible pathogenic mechanism in Fabry disease. However, the association of EMT with Fabry disease has not been elucidated yet. Expression level of EMT markers such as E‐cadherin, N‐cadherin, β‐catenin and α‐SMA in mouse renal glomerular mesangial cell (SV40MES13) significantly increased when treated with Gb3. Whereas, in human proximal renal tubular epithelial cells (HK‐2), expression of EMT markers were significantly altered when treated with lyso‐Gb3 rather than treated with Gb3. Additionally, we observed that the activation of TGF‐β, phospho‐AKT, and PI3K were highly elevated in these cells. When we treated recombinant α‐gal A with Gb3 or lyso‐Gb3, TGF‐β expression was reversed in HK2 cells. Our study demonstrates that Gb3 and lyso‐Gb3 can potentiate EMT‐like processes through AKT/PI3K signaling pathway in HK2 and SV40MES13 cells. Moreover, these findings suggest that lyso‐Gb3, rather than Gb3 may be a crucial role nephropathy of Fabry disease by inducing EMT and may contribute to a better understanding of the renal fibrosis.