Open AccessGlomerular endothelial cell senescence drives age‐related kidney disease through PAI‐1
Author(s) -
Cohen Camille,
Le Goff Océane,
Soysouvanh Frédéric,
Vasseur Florence,
Tanou Marine,
Nguyen Clément,
Amrouche Lucile,
Le Guen Julien,
SaltelFulero Oriana,
Meunier Tanguy,
NguyenKhoa Thao,
Rabant Marion,
Nochy Dominique,
Legendre Christophe,
Friedlander Gérard,
Childs Bennett G,
Baker Daren J,
Knebelmann Bertrand,
Anglicheau Dany,
Milliat Fabien,
Terzi Fabiola
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202114146
Subject(s) - humanities , art
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.