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

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.

Automated summary

The study uncovered a detrimental cross-talk between senescent glomerular endothelial cells and podocytes through PAI-1, affecting glomerular lesion development and podocyte loss in aged mice. Selective inactivation of PAI-1 or blocking its action prevented podocyte apoptosis, and depletion of senescent cells prevented podocyte loss in old transgenic mice. Furthermore, glomerular PAI-1 expression was predictive of poor outcomes in elderly donor kidney transplants and urinary PAI-1 levels were associated with age-related chronic kidney disease in elderly patients.