Kidney Week

Abstract: FR-PO109

Glomerular Endothelial Cell Senescence Drives Aged-Related Glomerulosclerosis via PAI1

Session Information

• Molecular Mechanisms of CKD - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Cohen, Camille, Hopital Necker, Paris, France

Camille Cohen,

• Le goff, Océane, Hopital Necker, Paris, France

Océane Le goff,

• Soysouvanh, Frederic, Institute for Radioprotection and Nuclear Safety, Fontenay-aux-Roses, France

Frederic Soysouvanh,

• Amrouche, Lucile, Hopital Necker, Paris, France

Lucile Amrouche,

• Karras, Alexandre, Hopital Europeen Georges Pompidou - Assistance Publique Hopitaux de Paris, Paris, France

Alexandre Karras,

• Nochy, Dominique, Hopital Europeen Georges Pompidou - Assistance Publique Hopitaux de Paris, Paris, France

Dominique Nochy,

• Milliat, Fabien, IRSN, Fontenay-aux Roses, France

Fabien Milliat,

• Terzi, Fabiola, Hopital Necker, Paris, France

Fabiola Terzi,

Background

Chronic kidney disease (CKD) is a major public health problem with a prevalence that dramatically increases with age. One of the most frequent histological lesions observed in elderly is glomerulosclerosis. However, its pathophysiology is still unclear. A recent study indicated that cellular senescence may be implicated since targeted apoptosis of senescent cells in aging murine models delays glomerulosclerosis. However, how cellular senescence triggers the development of glomerulosclerosis is unknown. Elucidating this issue was the aim of our study.

Methods

In this aim, we used several murine models including wild type and transgenic mice experiencing physiological and accelerated aging.

Results

As expected, 24 months-old mice developed sclerotic glomeruli as compared to 4 months-old mice. Beta-galactosidase and 53BP1 staining revealed increased glomerular cell senescence with age. Interestingly, colocalization experiments demonstrated that senescence interested almost exclusively endothelial cells. Consistently, we observed that endothelial glomerular cells were blocked in G1. This phenotype was associated with an increased expression of several components of the senescence associated secretory phenotype (SASP). Among these, plasminogen activator inhibitor 1 (PAI1), a senescence inducer and mediator, was particularly interesting, since its expression increased in endothelial cells. These results were confirmed in an experimental mouse model of accelerated aging (sublethal irradiation at 8 weeks and sacrifice 12 months later) as well as in patients treated with genotoxic. Interestingly, specific deletion of PAI1 in endothelial cells prevented cell senescence and the development of glomerulosclerosis during physiological aging in transgenic VECad-CreXPAI1^flox/flox mutant mice. Podocytes loss was also decreased in transgenic mice, suggesting a cross-talk between endothelial cells and podocytes.

Conclusion

In conclusion, our study uncovers the critical role played by endothelial senescence in the development of glomerulosclerosis and podocyte rarefaction in aging and identified PAI1 as a novel promising therapeutic target for preventing age-related CKD progression.

Funding

• Government Support - Non-U.S.