Renal Ischemia Induces Epigenetic Changes in Apoptotic, Proteolytic, and Mitochondrial Genes in Swine Scattered Tubular-like Cells
Background: Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells endowed with progenitor-like characteristics to repair injured parenchymal cells. STCs may be damaged and rendered ineffective by renal artery stenosis (RAS), but the underlying processes remain unclear. We hypo...
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MDPI AG
2022-05-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/11/1803 |
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| author | Kamalnath S. Rajagopalan Logan M. Glasstetter Xiang-Yang Zhu Roman Thaler Hui Tang Kyra L. Jordan Ishran M. Saadiq Sandra M. Herrmann Alejandro R. Chade Maria V. Irazabal Lilach O. Lerman Alfonso Eirin |
| author_facet | Kamalnath S. Rajagopalan Logan M. Glasstetter Xiang-Yang Zhu Roman Thaler Hui Tang Kyra L. Jordan Ishran M. Saadiq Sandra M. Herrmann Alejandro R. Chade Maria V. Irazabal Lilach O. Lerman Alfonso Eirin |
| author_sort | Kamalnath S. Rajagopalan |
| collection | DOAJ |
| description | Background: Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells endowed with progenitor-like characteristics to repair injured parenchymal cells. STCs may be damaged and rendered ineffective by renal artery stenosis (RAS), but the underlying processes remain unclear. We hypothesized that RAS alters the epigenetic landscape on DNA and the ensuing gene transcriptional profile of swine STCs. Methods: CD24+/CD133+ STCs were isolated from pig kidneys after 10 weeks of RAS or sham (<i>n</i> = 3 each) and their whole 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles were examined by 5mC and 5hmC immunoprecipitation sequencing (MeDIP-/hMeDIP-seq, respectively). A subsequent integrated (MeDIP/hMeDIP-seq/mRNA-seq) analysis was performed by comparing all online available gene sets using Gene Set Enrichment Analysis. Apoptosis, proteolysis, and mitochondrial structure and function were subsequently evaluated in vitro. Results: Differential expression (DE) analysis revealed 239 genes with higher and 236 with lower 5mC levels and 275 genes with higher and 315 with lower 5hmC levels in RAS-STCs compared to Normal-STCs (fold change ≥1.4 or ≤0.7, <i>p</i> ≤ 0.05). Integrated MeDIP-/hMeDIP-seq/mRNA-seq analysis identified several overlapping (DE-5mC/mRNA and DE-5hmC/mRNA levels) genes primarily implicated in apoptosis, proteolysis, and mitochondrial functions. Furthermore, RAS-STCs exhibited decreased apoptosis, mitochondrial matrix density, and ATP production, and increased intracellular amino acid concentration and ubiquitin expression. Conclusions: Renal ischemia induces epigenetic changes in apoptosis-, proteolysis-, and mitochondria-related genes, which correlate with alterations in the transcriptomic profile and corresponding function of swine STCs. These observations may contribute to developing novel targeted interventions to preserve the reparative potency of STCs in renal disease. |
| first_indexed | 2024-03-10T01:25:24Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-10T01:25:24Z |
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| spelling | doaj.art-fd7822a4328343f49ebe437f4d7282d92023-11-23T13:53:02ZengMDPI AGCells2073-44092022-05-011111180310.3390/cells11111803Renal Ischemia Induces Epigenetic Changes in Apoptotic, Proteolytic, and Mitochondrial Genes in Swine Scattered Tubular-like CellsKamalnath S. Rajagopalan0Logan M. Glasstetter1Xiang-Yang Zhu2Roman Thaler3Hui Tang4Kyra L. Jordan5Ishran M. Saadiq6Sandra M. Herrmann7Alejandro R. Chade8Maria V. Irazabal9Lilach O. Lerman10Alfonso Eirin11Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USADepartment of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55901, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USADepartment of Physiology and Biophysics, Medicine and Radiology, University of Mississippi Medical Center, Jackson, MS 55901, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USADivision of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USABackground: Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells endowed with progenitor-like characteristics to repair injured parenchymal cells. STCs may be damaged and rendered ineffective by renal artery stenosis (RAS), but the underlying processes remain unclear. We hypothesized that RAS alters the epigenetic landscape on DNA and the ensuing gene transcriptional profile of swine STCs. Methods: CD24+/CD133+ STCs were isolated from pig kidneys after 10 weeks of RAS or sham (<i>n</i> = 3 each) and their whole 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles were examined by 5mC and 5hmC immunoprecipitation sequencing (MeDIP-/hMeDIP-seq, respectively). A subsequent integrated (MeDIP/hMeDIP-seq/mRNA-seq) analysis was performed by comparing all online available gene sets using Gene Set Enrichment Analysis. Apoptosis, proteolysis, and mitochondrial structure and function were subsequently evaluated in vitro. Results: Differential expression (DE) analysis revealed 239 genes with higher and 236 with lower 5mC levels and 275 genes with higher and 315 with lower 5hmC levels in RAS-STCs compared to Normal-STCs (fold change ≥1.4 or ≤0.7, <i>p</i> ≤ 0.05). Integrated MeDIP-/hMeDIP-seq/mRNA-seq analysis identified several overlapping (DE-5mC/mRNA and DE-5hmC/mRNA levels) genes primarily implicated in apoptosis, proteolysis, and mitochondrial functions. Furthermore, RAS-STCs exhibited decreased apoptosis, mitochondrial matrix density, and ATP production, and increased intracellular amino acid concentration and ubiquitin expression. Conclusions: Renal ischemia induces epigenetic changes in apoptosis-, proteolysis-, and mitochondria-related genes, which correlate with alterations in the transcriptomic profile and corresponding function of swine STCs. These observations may contribute to developing novel targeted interventions to preserve the reparative potency of STCs in renal disease.https://www.mdpi.com/2073-4409/11/11/1803renal ischemiarenal artery stenosismitochondriascattered tubular-like cellsepigenetics |
| spellingShingle | Kamalnath S. Rajagopalan Logan M. Glasstetter Xiang-Yang Zhu Roman Thaler Hui Tang Kyra L. Jordan Ishran M. Saadiq Sandra M. Herrmann Alejandro R. Chade Maria V. Irazabal Lilach O. Lerman Alfonso Eirin Renal Ischemia Induces Epigenetic Changes in Apoptotic, Proteolytic, and Mitochondrial Genes in Swine Scattered Tubular-like Cells Cells renal ischemia renal artery stenosis mitochondria scattered tubular-like cells epigenetics |
| title | Renal Ischemia Induces Epigenetic Changes in Apoptotic, Proteolytic, and Mitochondrial Genes in Swine Scattered Tubular-like Cells |
| title_full | Renal Ischemia Induces Epigenetic Changes in Apoptotic, Proteolytic, and Mitochondrial Genes in Swine Scattered Tubular-like Cells |
| title_fullStr | Renal Ischemia Induces Epigenetic Changes in Apoptotic, Proteolytic, and Mitochondrial Genes in Swine Scattered Tubular-like Cells |
| title_full_unstemmed | Renal Ischemia Induces Epigenetic Changes in Apoptotic, Proteolytic, and Mitochondrial Genes in Swine Scattered Tubular-like Cells |
| title_short | Renal Ischemia Induces Epigenetic Changes in Apoptotic, Proteolytic, and Mitochondrial Genes in Swine Scattered Tubular-like Cells |
| title_sort | renal ischemia induces epigenetic changes in apoptotic proteolytic and mitochondrial genes in swine scattered tubular like cells |
| topic | renal ischemia renal artery stenosis mitochondria scattered tubular-like cells epigenetics |
| url | https://www.mdpi.com/2073-4409/11/11/1803 |
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