The Role of Indoleamine 2,3-Dioxygenase in Renal Tubular Epithelial Cells Senescence under Anoxia or Reoxygenation
Ischemia-reperfusion injury is the commonest form of acute kidney injury (AKI). Tubular epithelial cell senescence contributes to incomplete recovery from AKI and predisposes to subsequent chronic kidney disease. In cultures of primary proximal renal tubular epithelial cells (RPTECs) subjected to an...
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MDPI AG
2021-10-01
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| author | Theodoros Eleftheriadis Georgios Pissas Georgios Filippidis Vassilios Liakopoulos Ioannis Stefanidis |
| author_facet | Theodoros Eleftheriadis Georgios Pissas Georgios Filippidis Vassilios Liakopoulos Ioannis Stefanidis |
| author_sort | Theodoros Eleftheriadis |
| collection | DOAJ |
| description | Ischemia-reperfusion injury is the commonest form of acute kidney injury (AKI). Tubular epithelial cell senescence contributes to incomplete recovery from AKI and predisposes to subsequent chronic kidney disease. In cultures of primary proximal renal tubular epithelial cells (RPTECs) subjected to anoxia or reoxygenation, we evaluated the role of indoleamine 2,3-dioxygenase 1 (IDO) in cellular senescence. Proteins of interest were assessed with Western blotting or enzyme-linked immunosorbent assay or histochemically. Under anoxia or reoxygenation, IDO expression and activity were increased. Moreover, the two IDO-derived pathways, the general control nonderepressible 2 kinase (GCN2K) pathway and the aryl-hydrocarbon receptor (AhR) pathway, were also activated. A DNA damage response (DDR) took place and led to increased levels of the cell-cycle inhibitors p21 and p16, and senescence-associated β-galactosidase (SA-β-Gal) activity. Cell proliferation was inhibited, and more IL-6 was produced. The IDO inhibitor 1-DL-methyl-tryptophan ameliorated the DDR; decreased p21, p16, and SA-β-Gal activity; restored cell proliferation; and decreased IL-6 production. The AhR inhibitor CH223191 did not affect the above parameters. In conclusion, anoxia and the subsequent reoxygenation upregulate IDO. IDO depletes tryptophan and activates GCN2K. The latter enhances the anoxia- or reoxygenation-induced DDR, resulting in increased p21 and p16 expression and eventually leading to RPTEC senescence. Since cellular senescence affects AKI outcome, the role of IDO in cellular senescence and the possible therapeutic role of IDO inhibitors deserve further investigation. |
| first_indexed | 2024-03-10T06:42:14Z |
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| language | English |
| last_indexed | 2024-03-10T06:42:14Z |
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| series | Biomolecules |
| spelling | doaj.art-365011b8f8a14ed79ff7339043006dbb2023-11-22T17:34:53ZengMDPI AGBiomolecules2218-273X2021-10-011110152210.3390/biom11101522The Role of Indoleamine 2,3-Dioxygenase in Renal Tubular Epithelial Cells Senescence under Anoxia or ReoxygenationTheodoros Eleftheriadis0Georgios Pissas1Georgios Filippidis2Vassilios Liakopoulos3Ioannis Stefanidis4Department of Nephrology, Faculty of Medicine, University of Thessaly, 41110 Larissa, GreeceDepartment of Nephrology, Faculty of Medicine, University of Thessaly, 41110 Larissa, GreeceDepartment of Nephrology, Faculty of Medicine, University of Thessaly, 41110 Larissa, GreeceDepartment of Nephrology, Faculty of Medicine, University of Thessaly, 41110 Larissa, GreeceDepartment of Nephrology, Faculty of Medicine, University of Thessaly, 41110 Larissa, GreeceIschemia-reperfusion injury is the commonest form of acute kidney injury (AKI). Tubular epithelial cell senescence contributes to incomplete recovery from AKI and predisposes to subsequent chronic kidney disease. In cultures of primary proximal renal tubular epithelial cells (RPTECs) subjected to anoxia or reoxygenation, we evaluated the role of indoleamine 2,3-dioxygenase 1 (IDO) in cellular senescence. Proteins of interest were assessed with Western blotting or enzyme-linked immunosorbent assay or histochemically. Under anoxia or reoxygenation, IDO expression and activity were increased. Moreover, the two IDO-derived pathways, the general control nonderepressible 2 kinase (GCN2K) pathway and the aryl-hydrocarbon receptor (AhR) pathway, were also activated. A DNA damage response (DDR) took place and led to increased levels of the cell-cycle inhibitors p21 and p16, and senescence-associated β-galactosidase (SA-β-Gal) activity. Cell proliferation was inhibited, and more IL-6 was produced. The IDO inhibitor 1-DL-methyl-tryptophan ameliorated the DDR; decreased p21, p16, and SA-β-Gal activity; restored cell proliferation; and decreased IL-6 production. The AhR inhibitor CH223191 did not affect the above parameters. In conclusion, anoxia and the subsequent reoxygenation upregulate IDO. IDO depletes tryptophan and activates GCN2K. The latter enhances the anoxia- or reoxygenation-induced DDR, resulting in increased p21 and p16 expression and eventually leading to RPTEC senescence. Since cellular senescence affects AKI outcome, the role of IDO in cellular senescence and the possible therapeutic role of IDO inhibitors deserve further investigation.https://www.mdpi.com/2218-273X/11/10/1522senescenceindoleamine 2,3-dioxygenaseDNA damage responsep21p16ischemia-reperfusion |
| spellingShingle | Theodoros Eleftheriadis Georgios Pissas Georgios Filippidis Vassilios Liakopoulos Ioannis Stefanidis The Role of Indoleamine 2,3-Dioxygenase in Renal Tubular Epithelial Cells Senescence under Anoxia or Reoxygenation Biomolecules senescence indoleamine 2,3-dioxygenase DNA damage response p21 p16 ischemia-reperfusion |
| title | The Role of Indoleamine 2,3-Dioxygenase in Renal Tubular Epithelial Cells Senescence under Anoxia or Reoxygenation |
| title_full | The Role of Indoleamine 2,3-Dioxygenase in Renal Tubular Epithelial Cells Senescence under Anoxia or Reoxygenation |
| title_fullStr | The Role of Indoleamine 2,3-Dioxygenase in Renal Tubular Epithelial Cells Senescence under Anoxia or Reoxygenation |
| title_full_unstemmed | The Role of Indoleamine 2,3-Dioxygenase in Renal Tubular Epithelial Cells Senescence under Anoxia or Reoxygenation |
| title_short | The Role of Indoleamine 2,3-Dioxygenase in Renal Tubular Epithelial Cells Senescence under Anoxia or Reoxygenation |
| title_sort | role of indoleamine 2 3 dioxygenase in renal tubular epithelial cells senescence under anoxia or reoxygenation |
| topic | senescence indoleamine 2,3-dioxygenase DNA damage response p21 p16 ischemia-reperfusion |
| url | https://www.mdpi.com/2218-273X/11/10/1522 |
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