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

• Published in: EMBO molecular medicine Vol. 13; no. 11; pp. e14146 - n/a
• Main Authors: Cohen, Camille, Le Goff, Océane, Soysouvanh, Frédéric, Vasseur, Florence, Tanou, Marine, Nguyen, Clément, Amrouche, Lucile, Le Guen, Julien, Saltel‐Fulero, Oriana, Meunier, Tanguy, Nguyen‐Khoa, Thao, Rabant, Marion, Nochy, Dominique, Legendre, Christophe, Friedlander, Gérard, Childs, Bennett G, Baker, Daren J, Knebelmann, Bertrand, Anglicheau, Dany, Milliat, Fabien, Terzi, Fabiola
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.11.2021; EMBO Press; Wiley Open Access; John Wiley and Sons Inc; Springer Nature
• Subjects: Age; Aging; aging nephropathy; Allografts; Apoptosis; Biomarkers; Cell cycle; Cell division; Cyclin-dependent kinases; DNA damage; EMBO07; EMBO45; Endothelial cells; endothelial–podocyte cross‐talk; Geriatrics; Kidney diseases; Kidney transplantation; Kidney transplants; Lesions; Life Sciences; Morphology; Older people; PAI‐1; Physiology; Public health; Quality of life; Senescence; Transgenic mice; Transplants & implants; PAI‐1; senescence; aging nephropathy; endothelial–podocyte cross‐talk; kidney transplantation; Urogenital System; endothelial-podocyte cross-talk; senescence Subject Categories Autophagy & Cell Death; PAI-1; aging nephropathy endothelial-podocyte cross-talk kidney transplantation PAI-1 senescence Subject Categories Autophagy & Cell Death Urogenital System
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.202114146

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. SYNOPSIS Kidneys develop lesions with age, and in particular glomerulosclerosis, but the molecular mechanisms involved in the deterioration process are unclear. Here, an unexpected role for glomerular endothelial cells during aging was uncovered. Senescent glomerular endothelial cells increased with age, whereas the number of podocytes decreased. The existence of a detrimental crosstalk between senescent glomerular endothelial cells and podocyte was demonstrated in vivo and in vitro . Depletion of senescent cells prevented podocyte loss with age. PAI‐1 was a critical mediator of this cross‐stalk, and its selective inactivation in endothelial cell preserved kidneys from glomerulosclerosis during aging. PAI‐1 immunostaining predicted kidney allograft dysfunction after transplantation from elderly donors. PAI‐1 excretion was increased in the urine of elderly patients with recognized aging nephropathy. Graphical Abstract Kidneys develop lesions with age, and in particular glomerulosclerosis, but the molecular mechanisms involved in the deterioration process are unclear. Here, an unexpected role for glomerular endothelial cells during aging was uncovered.