title: Substrate-specific gene expression profiles in different kidney cell types are associated with Fabry disease.
abstract: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene encoding the α-galactosidase A (α-Gal A) lysosomal enzyme, which results in globotriaosylceramide (Gb3) storage in vascular endothelial cells and different cell types throughout the body. Involvement of the kidney and heart is life threatening, and fibrosis of these organs is considered to be involved in the pathogenesis of Fabry disease. An increased concentration of deacylated Gb3 (lyso‑Gb3) in the plasma of symptomatic patients has also been suggested as a causative molecular event. To elucidate the molecular mechanisms involved in renal fibrosis in Fabry disease, the present analyzed the changes in global gene expression prior to and following Gb3 or lyso‑Gb3 treatment in two types of kidney cell lines, human proximal renal tubular epithelial (HK‑2) and mouse renal glomerular mesangial (SV40 MES 13) cells. Gb3 and lyso‑Gb3 treatment regulated the expression of 199 and 328 genes in each cell type, demonstrating a >2.0‑fold change. The majority of the biological functions of the regulated genes were associated with fibrogenesis or epithelial‑mesenchymal transition (EMT). The gene expression patterns of sphingolipid‑treated HK‑2 cells were distinguishable from the patterns in the SV40 MES 13 cells. Several genes associated with the EMT were selected and evaluated further in kidney cells and in Fabry mouse kidney tissues. In the SV40 MES 13 cells, the DLL1, F8, and HOXA11 genes were downregulated, and FOXP2 was upregulated by treatment with Gb3 or lyso‑Gb3. In the HK‑2 cells, the ADAMTS6, BEST1, IL4, and MYH11 genes were upregulated. Upregulation of the FOXP2, COL15A1, IL4, and MYH11 genes was also observed in the Fabry mouse kidney tissues. The gene expression profiles in kidney cells following the addition of Gb3 or lyso‑Gb3 revealed substrate‑specific and cell‑specific patterns. These findings suggested that Gb3 and lyso‑Gb3 lead to renal fibrosis in Fabry disease through different biochemical modulations.
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158‑710, Republic of Korea.
authors.forename: Youn-Jeong
authors.initials: YJ
authors.lastname: Shin
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158‑710, Republic of Korea.
authors.forename: Yeo Jin
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158‑710, Republic of Korea.
authors.forename: Namhee
authors.initials: N
authors.lastname: Jung
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158‑710, Republic of Korea.
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158‑710, Republic of Korea.
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Park
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158‑710, Republic of Korea.
authors.forename: Sung-Chul
authors.initials: SC
authors.lastname: Jung
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071096:ADAMTS Proteins; D000818:Animals; D000075002:Bestrophins; D002135:Calcium-Binding Proteins; D002461:Cell Line, Transformed; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D000795:Fabry Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006017:Glycolipids / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D058977:Molecular Sequence Annotation; D009928:Organ Specificity; D015398:Signal Transduction; D013107:Sphingolipids / Q000494:pharmacology; D059467:Transcriptome; D014281:Trihexosylceramides / Q000494:pharmacology
chemical_list: C113133:BEST1 protein, human; D000075002:Bestrophins; D002135:Calcium-Binding Proteins; D018118:Chloride Channels; C512925:Dlk1 protein, mouse; D005136:Eye Proteins; D006017:Glycolipids; D018398:Homeodomain Proteins; C094041:Hoxa11 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D013107:Sphingolipids; D014281:Trihexosylceramides; C063288:globotriaosyl lysosphingolipid; C018549:globotriaosylceramide; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C121533:Adamts6 protein, human