TY - JOUR
T1 - Glomerular endothelial cell senescence drives age-related kidney disease through PAI-1
AU - Cohen, Camille
AU - Le Goff, Océane
AU - Soysouvanh, Frédéric
AU - Vasseur, Florence
AU - Tanou, Marine
AU - Nguyen, Clément
AU - Amrouche, Lucile
AU - Le Guen, Julien
AU - Saltel-Fulero, Oriana
AU - Meunier, Tanguy
AU - Nguyen-Khoa, Thao
AU - Rabant, Marion
AU - Nochy, Dominique
AU - Legendre, Christophe
AU - Friedlander, Gérard
AU - Childs, Bennett G.
AU - Baker, Daren J.
AU - Knebelmann, Bertrand
AU - Anglicheau, Dany
AU - Milliat, Fabien
AU - Terzi, Fabiola
N1 - Publisher Copyright:
© 2021 The Authors Published under the terms of the CC BY 4.0 license
PY - 2021/11/8
Y1 - 2021/11/8
N2 - 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.
AB - 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.
KW - PAI-1
KW - aging nephropathy
KW - endothelial–podocyte cross-talk
KW - kidney transplantation
KW - senescence
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U2 - 10.15252/emmm.202114146
DO - 10.15252/emmm.202114146
M3 - Article
C2 - 34725920
AN - SCOPUS:85118358563
SN - 1757-4676
VL - 13
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 11
M1 - e14146
ER -