Glomerular endothelial cell senescence drives age‐related kidney disease through PAI‐1
Abstract The mechanisms underlying the development of glomerular lesions during aging are largely unknown. It has been suggested that senescence might play a role, but the pathophysiological link between senescence and lesion development remains unexplained. Here, we uncovered an unexpected role for...
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Springer Nature
2021-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202114146 |
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| author | Camille Cohen Océane Le Goff Frédéric Soysouvanh Florence Vasseur Marine Tanou Clément Nguyen Lucile Amrouche Julien Le Guen Oriana Saltel‐Fulero Tanguy Meunier Thao Nguyen‐Khoa Marion Rabant Dominique Nochy Christophe Legendre Gérard Friedlander Bennett G Childs Daren J Baker Bertrand Knebelmann Dany Anglicheau Fabien Milliat Fabiola Terzi |
| author_facet | Camille Cohen Océane Le Goff Frédéric Soysouvanh Florence Vasseur Marine Tanou Clément Nguyen Lucile Amrouche Julien Le Guen Oriana Saltel‐Fulero Tanguy Meunier Thao Nguyen‐Khoa Marion Rabant Dominique Nochy Christophe Legendre Gérard Friedlander Bennett G Childs Daren J Baker Bertrand Knebelmann Dany Anglicheau Fabien Milliat Fabiola Terzi |
| author_sort | Camille Cohen |
| collection | DOAJ |
| description | Abstract The mechanisms underlying the development of glomerular lesions during aging are largely unknown. It has been suggested that senescence might play a role, but the pathophysiological link between senescence and lesion development remains unexplained. Here, we uncovered an unexpected role for glomerular endothelial cells during aging. In fact, we discovered a detrimental cross‐talk between senescent endothelial cells and podocytes, through PAI‐1. In vivo, selective inactivation of PAI‐1 in endothelial cells protected glomeruli from lesion development and podocyte loss in aged mice. In vitro, blocking PAI‐1 in supernatants from senescent endothelial cells prevented podocyte apoptosis. Consistently, depletion of senescent cells prevented podocyte loss in old p16 INK‐ATTAC transgenic mice. Importantly, these experimental findings are relevant to humans. We showed that glomerular PAI‐1 expression was predictive of poor outcomes in transplanted kidneys from elderly donors. In addition, we observed that in elderly patients, urinary PAI‐1 was associated with age‐related chronic kidney disease. Altogether, these results uncover a novel mechanism of kidney disease and identify PAI‐1 as a promising biomarker of kidney dysfunction in allografts from elderly donors. |
| format | Article |
| id | doaj-art-eff346c772ac4a2782e8d2599fcc5044 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-eff346c772ac4a2782e8d2599fcc50442025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-11-01131112010.15252/emmm.202114146Glomerular endothelial cell senescence drives age‐related kidney disease through PAI‐1Camille Cohen0Océane Le Goff1Frédéric Soysouvanh2Florence Vasseur3Marine Tanou4Clément Nguyen5Lucile Amrouche6Julien Le Guen7Oriana Saltel‐Fulero8Tanguy Meunier9Thao Nguyen‐Khoa10Marion Rabant11Dominique Nochy12Christophe Legendre13Gérard Friedlander14Bennett G Childs15Daren J Baker16Bertrand Knebelmann17Dany Anglicheau18Fabien Milliat19Fabiola Terzi20Université de Paris, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Département “Croissance et Signalisation”Université de Paris, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Département “Croissance et Signalisation”Institut de Radioprotection et de Sureté Nucléaire (IRSN), Laboratoire Radiobiologie des Expositions MédicaleUniversité de Paris, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Département “Croissance et Signalisation”Université de Paris, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Département “Croissance et Signalisation”Université de Paris, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Département “Croissance et Signalisation”Université de Paris, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Département “Croissance et Signalisation”Service de Gériatrie, Hôpital Européen Georges Pompidou, AP‐HP Centre, Université de ParisService de Gériatrie, Hôpital Européen Georges Pompidou, AP‐HP Centre, Université de ParisService de Gériatrie, Hôpital Européen Georges Pompidou, AP‐HP Centre, Université de ParisUniversité de Paris, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Département “Croissance et Signalisation”Université de Paris, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Département “Croissance et Signalisation”Service d'Anatomo‐Pathologie, Hôpital Européen George Pompidou, AP‐HP Centre, Université de ParisUniversité de Paris, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Département “Croissance et Signalisation”Université de Paris, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Département “Croissance et Signalisation”Department of Pediatrics, Mayo Clinic College of MedicineDepartment of Pediatrics, Mayo Clinic College of MedicineUniversité de Paris, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Département “Croissance et Signalisation”Université de Paris, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Département “Croissance et Signalisation”Institut de Radioprotection et de Sureté Nucléaire (IRSN), Laboratoire Radiobiologie des Expositions MédicaleUniversité de Paris, INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades (INEM), Département “Croissance et Signalisation”Abstract The mechanisms underlying the development of glomerular lesions during aging are largely unknown. It has been suggested that senescence might play a role, but the pathophysiological link between senescence and lesion development remains unexplained. Here, we uncovered an unexpected role for glomerular endothelial cells during aging. In fact, we discovered a detrimental cross‐talk between senescent endothelial cells and podocytes, through PAI‐1. In vivo, selective inactivation of PAI‐1 in endothelial cells protected glomeruli from lesion development and podocyte loss in aged mice. In vitro, blocking PAI‐1 in supernatants from senescent endothelial cells prevented podocyte apoptosis. Consistently, depletion of senescent cells prevented podocyte loss in old p16 INK‐ATTAC transgenic mice. Importantly, these experimental findings are relevant to humans. We showed that glomerular PAI‐1 expression was predictive of poor outcomes in transplanted kidneys from elderly donors. In addition, we observed that in elderly patients, urinary PAI‐1 was associated with age‐related chronic kidney disease. Altogether, these results uncover a novel mechanism of kidney disease and identify PAI‐1 as a promising biomarker of kidney dysfunction in allografts from elderly donors.https://doi.org/10.15252/emmm.202114146aging nephropathyendothelial–podocyte cross‐talkkidney transplantationPAI‐1senescence |
| spellingShingle | Camille Cohen Océane Le Goff Frédéric Soysouvanh Florence Vasseur Marine Tanou Clément Nguyen Lucile Amrouche Julien Le Guen Oriana Saltel‐Fulero Tanguy Meunier Thao Nguyen‐Khoa Marion Rabant Dominique Nochy Christophe Legendre Gérard Friedlander Bennett G Childs Daren J Baker Bertrand Knebelmann Dany Anglicheau Fabien Milliat Fabiola Terzi Glomerular endothelial cell senescence drives age‐related kidney disease through PAI‐1 EMBO Molecular Medicine aging nephropathy endothelial–podocyte cross‐talk kidney transplantation PAI‐1 senescence |
| title | Glomerular endothelial cell senescence drives age‐related kidney disease through PAI‐1 |
| title_full | Glomerular endothelial cell senescence drives age‐related kidney disease through PAI‐1 |
| title_fullStr | Glomerular endothelial cell senescence drives age‐related kidney disease through PAI‐1 |
| title_full_unstemmed | Glomerular endothelial cell senescence drives age‐related kidney disease through PAI‐1 |
| title_short | Glomerular endothelial cell senescence drives age‐related kidney disease through PAI‐1 |
| title_sort | glomerular endothelial cell senescence drives age related kidney disease through pai 1 |
| topic | aging nephropathy endothelial–podocyte cross‐talk kidney transplantation PAI‐1 senescence |
| url | https://doi.org/10.15252/emmm.202114146 |
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