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Substrate-specific gene expression profiles in different kidney cell types are associated with Fabry disease
- Source :
- Molecular Medicine Reports
- Publication Year :
- 2015
- Publisher :
- Spandidos Publications, 2015.
-
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.
- Subjects :
- Male
Cancer Research
mesangial cell
Biochemistry
Mice
chemistry.chemical_compound
ADAMTS Proteins
Bestrophins
Cell Line, Transformed
globotriaosylceramide
Regulation of gene expression
Kidney
Trihexosylceramides
Articles
Kidney Tubules
medicine.anatomical_structure
Oncology
Organ Specificity
Mesangial Cells
Intercellular Signaling Peptides and Proteins
gene expression profile
Molecular Medicine
Signal Transduction
kidney
Cell type
Epithelial-Mesenchymal Transition
Globotriaosylceramide
Mice, Transgenic
Biology
Chloride Channels
Genetics
Renal fibrosis
medicine
Animals
Humans
globotriaosylsphingosine
Epithelial–mesenchymal transition
Eye Proteins
Molecular Biology
Homeodomain Proteins
Sphingolipids
Fabry disease
Gene Expression Profiling
epithelial cell
Calcium-Binding Proteins
Epithelial Cells
Molecular Sequence Annotation
medicine.disease
Molecular biology
Gene expression profiling
ADAM Proteins
Disease Models, Animal
Gene Expression Regulation
chemistry
Glycolipids
Transcriptome
Subjects
Details
- ISSN :
- 17913004 and 17912997
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Molecular Medicine Reports
- Accession number :
- edsair.doi.dedup.....c21f0b7b024199dab537a93c9b6356ec