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

Camille Cohen (1, 2) , Océane Le Goff (1) , Frédéric Soysouvanh (3) , Florence Vasseur (1) , Marine Tanou (1) , Clément Nguyen (1) , Lucile Amrouche (4) , Julien Le Guen (5, 6) , Oriana Saltel‐fulero (7) , Tanguy Meunier (7) , Thao Nguyen‐khoa (4) , Marion Rabant (8) , Dominique Nochy (9, 5) , Christophe Legendre (4, 9) , Gérard Friedlander (10) , Bennett G Childs (11) , Daren J Baker (11) , Bertrand Knebelmann (2) , Dany Anglicheau (1, 4) , Fabien Milliat (3) , Fabiola Terzi (1)

1 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
2 Service Néphrologie et transplantation rénale Adultes [CHU Necker]
3 IRSN/PSE-SANTE/SERAMED/LRMed - Laboratoire de Radiobiologie des expositions médicales
4 Hôpital Necker - Enfants Malades [AP-HP]
5 HEGP - Hôpital Européen Georges Pompidou [APHP]
6 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
7 Service de gériatrie
8 Département de Pathologie [CHU Necker]
9 UPCité - Université Paris Cité
10 UFR Médecine UPCité - UFR Médecine [Santé] - Université Paris Cité
11 Mayo Clinic College of Medicine

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.

Mots clés: aging nephropathy endothelial-podocyte cross-talk kidney transplantation PAI-1 senescence Subject Categories Autophagy & Cell Death Urogenital System; aging nephropathy; endothelial-podocyte cross-talk; kidney transplantation; PAI-1; senescence Subject Categories Autophagy & Cell Death; Urogenital System

Domaines: Sciences du Vivant [q-bio]

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⟩