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Article Dans Une Revue EMBO Molecular Medicine Année : 2021

Glomerular endothelial cell senescence drives age‐related kidney disease through PAI‐1

Thao Nguyen‐khoa
Daren J Baker
Fabiola Terzi

Résumé

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.
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irsn-03980928 , version 1 (09-02-2023)

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Camille Cohen, Océane Le Goff, Frédéric Soysouvanh, Florence Vasseur, Marine Tanou, et al.. Glomerular endothelial cell senescence drives age‐related kidney disease through PAI‐1. EMBO Molecular Medicine, 2021, 13 (11), ⟨10.15252/emmm.202114146⟩. ⟨irsn-03980928⟩
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