Implications of Senescent Cell Burden and NRF2 Pathway in Uremic Calcification: A Translational Study
Increased senescent cell burden and dysregulation of the nuclear factor erythroid 2–related factor 2 (NRF2) pathway have been associated with numerous age-related pathologies; however, their role in promoting vascular calcification (VC) in chronic kidney disease (CKD) has yet to be determined. We in...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
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MDPI AG
2023-02-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/4/643 |
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| author | Jonas Laget Sam Hobson Karen Muyor Flore Duranton Irene Cortijo Piotr Bartochowski Bernard Jover Anne-Dominique Lajoix Magnus Söderberg Thomas Ebert Peter Stenvinkel Àngel Argilés Karolina Kublickiene Nathalie Gayrard |
| author_facet | Jonas Laget Sam Hobson Karen Muyor Flore Duranton Irene Cortijo Piotr Bartochowski Bernard Jover Anne-Dominique Lajoix Magnus Söderberg Thomas Ebert Peter Stenvinkel Àngel Argilés Karolina Kublickiene Nathalie Gayrard |
| author_sort | Jonas Laget |
| collection | DOAJ |
| description | Increased senescent cell burden and dysregulation of the nuclear factor erythroid 2–related factor 2 (NRF2) pathway have been associated with numerous age-related pathologies; however, their role in promoting vascular calcification (VC) in chronic kidney disease (CKD) has yet to be determined. We investigated whether senescence and NRF2 pathways may serve as drivers of uremia-induced VC using three complementary approaches: a novel model of induced VC in 5/6-nephrectomized rats supplemented with high phosphate and vitamin D; epigastric arteries from CKD patients with established medial calcification; and vascular smooth muscle cells (VSMCs) incubated with uremic serum. Expression of p16<sup>Ink4a</sup> and p21<sup>Cip1</sup>, as well as γ-H2A-positive cells, confirmed increased senescent cell burden at the site of calcium deposits in aortic sections in rats, and was similarly observed in calcified epigastric arteries from CKD patients through increased p16<sup>Ink4a</sup> expression. However, uremic serum-induced VSMC calcification was not accompanied by senescence. Expression of NRF2 and downstream genes, <i>Nqo1</i> and <i>Sod1</i>, was associated with calcification in uremic rats, while no difference was observed between calcified and non-calcified EAs. Conversely, in vitro uremic serum-driven VC was associated with depleted NRF2 expression. Together, our data strengthen the importance of senescence and NRF2 pathways as potential therapeutic options to combat VC in CKD. |
| first_indexed | 2024-03-11T09:01:14Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T09:01:14Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-c25174718b5240b4abe46e889bee39e32023-11-16T19:45:14ZengMDPI AGCells2073-44092023-02-0112464310.3390/cells12040643Implications of Senescent Cell Burden and NRF2 Pathway in Uremic Calcification: A Translational StudyJonas Laget0Sam Hobson1Karen Muyor2Flore Duranton3Irene Cortijo4Piotr Bartochowski5Bernard Jover6Anne-Dominique Lajoix7Magnus Söderberg8Thomas Ebert9Peter Stenvinkel10Àngel Argilés11Karolina Kublickiene12Nathalie Gayrard13RD-Néphrologie, 34090 Montpellier, FranceDivision of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 52 Stockholm, SwedenRD-Néphrologie, 34090 Montpellier, FranceRD-Néphrologie, 34090 Montpellier, FranceRD-Néphrologie, 34090 Montpellier, FranceRD-Néphrologie, 34090 Montpellier, FranceRD-Néphrologie, 34090 Montpellier, FranceBiocommunication in Cardio-Metabolism (BC2M), University of Montpellier, 34090 Montpellier, FrancePathology, Clinical Pharmacology and Safety Sciences, R&D AstraZeneca, 431 50 Gothenburg, SwedenDivision of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 52 Stockholm, SwedenDivision of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 52 Stockholm, SwedenRD-Néphrologie, 34090 Montpellier, FranceDivision of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 52 Stockholm, SwedenRD-Néphrologie, 34090 Montpellier, FranceIncreased senescent cell burden and dysregulation of the nuclear factor erythroid 2–related factor 2 (NRF2) pathway have been associated with numerous age-related pathologies; however, their role in promoting vascular calcification (VC) in chronic kidney disease (CKD) has yet to be determined. We investigated whether senescence and NRF2 pathways may serve as drivers of uremia-induced VC using three complementary approaches: a novel model of induced VC in 5/6-nephrectomized rats supplemented with high phosphate and vitamin D; epigastric arteries from CKD patients with established medial calcification; and vascular smooth muscle cells (VSMCs) incubated with uremic serum. Expression of p16<sup>Ink4a</sup> and p21<sup>Cip1</sup>, as well as γ-H2A-positive cells, confirmed increased senescent cell burden at the site of calcium deposits in aortic sections in rats, and was similarly observed in calcified epigastric arteries from CKD patients through increased p16<sup>Ink4a</sup> expression. However, uremic serum-induced VSMC calcification was not accompanied by senescence. Expression of NRF2 and downstream genes, <i>Nqo1</i> and <i>Sod1</i>, was associated with calcification in uremic rats, while no difference was observed between calcified and non-calcified EAs. Conversely, in vitro uremic serum-driven VC was associated with depleted NRF2 expression. Together, our data strengthen the importance of senescence and NRF2 pathways as potential therapeutic options to combat VC in CKD.https://www.mdpi.com/2073-4409/12/4/643vascular calcificationkidney failureNRF2senescencesubtotal nephrectomy |
| spellingShingle | Jonas Laget Sam Hobson Karen Muyor Flore Duranton Irene Cortijo Piotr Bartochowski Bernard Jover Anne-Dominique Lajoix Magnus Söderberg Thomas Ebert Peter Stenvinkel Àngel Argilés Karolina Kublickiene Nathalie Gayrard Implications of Senescent Cell Burden and NRF2 Pathway in Uremic Calcification: A Translational Study Cells vascular calcification kidney failure NRF2 senescence subtotal nephrectomy |
| title | Implications of Senescent Cell Burden and NRF2 Pathway in Uremic Calcification: A Translational Study |
| title_full | Implications of Senescent Cell Burden and NRF2 Pathway in Uremic Calcification: A Translational Study |
| title_fullStr | Implications of Senescent Cell Burden and NRF2 Pathway in Uremic Calcification: A Translational Study |
| title_full_unstemmed | Implications of Senescent Cell Burden and NRF2 Pathway in Uremic Calcification: A Translational Study |
| title_short | Implications of Senescent Cell Burden and NRF2 Pathway in Uremic Calcification: A Translational Study |
| title_sort | implications of senescent cell burden and nrf2 pathway in uremic calcification a translational study |
| topic | vascular calcification kidney failure NRF2 senescence subtotal nephrectomy |
| url | https://www.mdpi.com/2073-4409/12/4/643 |
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