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

EMBO Mol Med. 2021 Nov 8;13(11):e14146. doi: 10.15252/emmm.202114146. Epub 2021 Nov 2.


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.

Keywords: PAI-1; aging nephropathy; endothelial-podocyte cross-talk; kidney transplantation; senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Cellular Senescence
  • Endothelial Cells
  • Humans
  • Kidney Diseases*
  • Kidney Glomerulus
  • Mice
  • Plasminogen Activator Inhibitor 1
  • Podocytes*


  • Plasminogen Activator Inhibitor 1