Substrate-specific gene expression profiles in different kidney cell types are associated with Fabry disease

Area of Science:

• Nephrology
• Genetics
• Molecular Biology

Background:

• Fabry disease is an X-linked lysosomal storage disorder due to alpha-galactosidase A deficiency.
• Accumulation of globotriaosylceramide (Gb3) and lyso-Gb3 in cells contributes to organ damage, particularly renal fibrosis.
• The precise molecular mechanisms driving renal fibrosis in Fabry disease remain incompletely understood.

Purpose of the Study:

• To investigate the molecular mechanisms underlying renal fibrosis in Fabry disease.
• To analyze global gene expression changes induced by Gb3 and lyso-Gb3 in kidney cells.
• To identify specific genes and pathways involved in fibrogenesis and epithelial-mesenchymal transition (EMT).

Main Methods:

• Global gene expression analysis using RNA sequencing.
• Treatment of human proximal renal tubular epithelial (HK-2) and mouse renal glomerular mesangial (SV40 MES 13) cells with Gb3 and lyso-Gb3.
• Validation of selected gene expression changes in kidney cells and Fabry mouse kidney tissues.

Main Results:

• Gb3 and lyso-Gb3 treatments altered the expression of hundreds of genes in kidney cell lines, predominantly related to fibrogenesis and EMT.
• Gene expression patterns were distinct between HK-2 and SV40 MES 13 cells, indicating cell-specific responses.
• Several EMT-associated genes (e.g., FOXP2, COL15A1, IL4, MYH11) were upregulated in kidney cells and Fabry mouse tissues.

Conclusions:

• Gb3 and lyso-Gb3 induce renal fibrosis through distinct molecular modulations in a cell-specific manner.
• The identified gene expression profiles provide insights into the pathogenesis of Fabry disease-associated kidney fibrosis.
• These findings highlight potential therapeutic targets for mitigating renal fibrosis in Fabry disease.