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

Shin YJ, Jeon YJ, Jung N, Park JW, Park HY, Jung SC - Mol Med Rep (2015)

Bottom Line: The majority of the biological functions of the regulated genes were associated with fibrogenesis or epithelial‑mesenchymal transition (EMT).In the HK‑2 cells, the ADAMTS6, BEST1, IL4, and MYH11 genes were upregulated.The gene expression profiles in kidney cells following the addition of Gb3 or lyso‑Gb3 revealed substrate‑specific and cell‑specific patterns.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158‑710, Republic of Korea.

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.

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Gene ontology analyses based on microarray data using DAVID Bioinformatics Resources 6.7. Gene ontology profile in SV40 MES 13 cells treated with (A) Gb3 or (B) lyso-Gb3, and in HK-2 cells treated with (C) Gb3 or (D) lyso-Gb3. The number of upregulated or downregulated genes in each group among the total of significantly regulated genes is expressed as the ratio (%) of the Gb3-treated, vs. control cells or lyso-Gb3-treated, vs. control cells. Gb3, globotriaosylceramide; lyso-Gb3, deacylated Gb3.
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f1-mmr-12-04-5049: Gene ontology analyses based on microarray data using DAVID Bioinformatics Resources 6.7. Gene ontology profile in SV40 MES 13 cells treated with (A) Gb3 or (B) lyso-Gb3, and in HK-2 cells treated with (C) Gb3 or (D) lyso-Gb3. The number of upregulated or downregulated genes in each group among the total of significantly regulated genes is expressed as the ratio (%) of the Gb3-treated, vs. control cells or lyso-Gb3-treated, vs. control cells. Gb3, globotriaosylceramide; lyso-Gb3, deacylated Gb3.

Mentions: A total of 39,429 genes were detected in the SV40 MES 13 cells, of which 2,991 were significant. The majority of the upregulated genes were associated with 'ECM', 'cell migration,' 'cell differentiation' or 'immune response'. The majority of the of the downregulated genes were associated with 'ECM', 'immune response' or 'cell migration' (Fig. 1A and B).


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

Shin YJ, Jeon YJ, Jung N, Park JW, Park HY, Jung SC - Mol Med Rep (2015)

Gene ontology analyses based on microarray data using DAVID Bioinformatics Resources 6.7. Gene ontology profile in SV40 MES 13 cells treated with (A) Gb3 or (B) lyso-Gb3, and in HK-2 cells treated with (C) Gb3 or (D) lyso-Gb3. The number of upregulated or downregulated genes in each group among the total of significantly regulated genes is expressed as the ratio (%) of the Gb3-treated, vs. control cells or lyso-Gb3-treated, vs. control cells. Gb3, globotriaosylceramide; lyso-Gb3, deacylated Gb3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581816&req=5

f1-mmr-12-04-5049: Gene ontology analyses based on microarray data using DAVID Bioinformatics Resources 6.7. Gene ontology profile in SV40 MES 13 cells treated with (A) Gb3 or (B) lyso-Gb3, and in HK-2 cells treated with (C) Gb3 or (D) lyso-Gb3. The number of upregulated or downregulated genes in each group among the total of significantly regulated genes is expressed as the ratio (%) of the Gb3-treated, vs. control cells or lyso-Gb3-treated, vs. control cells. Gb3, globotriaosylceramide; lyso-Gb3, deacylated Gb3.
Mentions: A total of 39,429 genes were detected in the SV40 MES 13 cells, of which 2,991 were significant. The majority of the upregulated genes were associated with 'ECM', 'cell migration,' 'cell differentiation' or 'immune response'. The majority of the of the downregulated genes were associated with 'ECM', 'immune response' or 'cell migration' (Fig. 1A and B).

Bottom Line: The majority of the biological functions of the regulated genes were associated with fibrogenesis or epithelial‑mesenchymal transition (EMT).In the HK‑2 cells, the ADAMTS6, BEST1, IL4, and MYH11 genes were upregulated.The gene expression profiles in kidney cells following the addition of Gb3 or lyso‑Gb3 revealed substrate‑specific and cell‑specific patterns.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158‑710, Republic of Korea.

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.

Show MeSH
Related in: MedlinePlus