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  • Glomerular endothelial cell senescence drives age-related kidney disease through PAI-1.

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

EMBO molecular medicine (2021-11-03)
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
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.

MATERIALS
Product Number
Brand
Product Description

Roche
In Situ Cell Death Detection Kit, Fluorescein, sufficient for ≤50 tests, suitable for detection
Sigma-Aldrich
Phalloidin–Tetramethylrhodamine B isothiocyanate, sequence from Amanita phalloides(synthetic: peptide sequence)
Sigma-Aldrich
Tiplaxtinin, ≥98% (HPLC)