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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	aging nephropathy endothelial–podocyte cross‐talk kidney transplantation PAI‐1 senescence Medicine (General) R5-920 Genetics QH426-470
Acceso en línea:	https://doaj.org/article/eff346c772ac4a2782e8d2599fcc5044
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spelling	oai:doaj.org-article:eff346c772ac4a2782e8d2599fcc50442021-11-08T09:27:45ZGlomerular endothelial cell senescence drives age‐related kidney disease through PAI‐11757-46841757-467610.15252/emmm.202114146https://doaj.org/article/eff346c772ac4a2782e8d2599fcc50442021-11-01T00:00:00Zhttps://doi.org/10.15252/emmm.202114146https://doaj.org/toc/1757-4676https://doaj.org/toc/1757-4684Abstract 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.Camille CohenOcéane Le GoffFrédéric SoysouvanhFlorence VasseurMarine TanouClément NguyenLucile AmroucheJulien Le GuenOriana Saltel‐FuleroTanguy MeunierThao Nguyen‐KhoaMarion RabantDominique NochyChristophe LegendreGérard FriedlanderBennett G ChildsDaren J BakerBertrand KnebelmannDany AnglicheauFabien MilliatFabiola TerziWileyarticleaging nephropathyendothelial–podocyte cross‐talkkidney transplantationPAI‐1senescenceMedicine (General)R5-920GeneticsQH426-470ENEMBO Molecular Medicine, Vol 13, Iss 11, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	aging nephropathy endothelial–podocyte cross‐talk kidney transplantation PAI‐1 senescence Medicine (General) R5-920 Genetics QH426-470
spellingShingle	aging nephropathy endothelial–podocyte cross‐talk kidney transplantation PAI‐1 senescence Medicine (General) R5-920 Genetics QH426-470 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
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
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
title	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_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_sort	glomerular endothelial cell senescence drives age‐related kidney disease through pai‐1
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/eff346c772ac4a2782e8d2599fcc5044
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Glomerular endothelial cell senescence drives age‐related kidney disease through PAI‐1

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