Cooperative Action of p53 and Autophagy Delays Kidney Aging by Suppressing DNA Damage and the Senescence-Associated Secretory Phenotype

Le résumé fourni par la source

Background: p53 is a crucial tumor suppressor and has long been recognized to suppress cancer through the induction of cell-cycle-arrest or apoptosis programs. Recently the diverse and global functions of p53 in the kidney under disease pathogenesis, especially acute kidney injury (AKI), has been studied intensively; however, its pathophysiological role in kidney aging remains uncertain. Methods: Using proximal tubular epithelial cell (PTEC)-specific p53-deficient (p53F/F-TSKO) mice and PTEC-specific atg5-deficient (atg5F/F-TSKO) mice, we investigated the role of p53 and a possible interplay between p53 and autophagy in the aged kidney. To examine whether and how the interaction between p53 and autophagy impinges on kidney aging, we assessed the phenotypes of PTEC-specific p53 and atg5-deficient (TSDKO) mice at 24 months. Results: p53F/F-TSKO at 24 months exhibited DNA damage, thereby upregulating autophagy. On the other hand, aged atg5F/F-TSKO mice activated p53. Aged TSDKO mice deteriorated renal histology and function, accompanied by accelerated tubular senescence and the senescence-associated secretory phenotype (SASP), thus facilitating tertiary lymphoid tissues (TLTs) development. Mechanistically, autophagy suppressed the SASP by degrading cytoplasmic chromatin fragments (CCFs) in aged kidneys. Conclusions: p53 and autophagy cooperatively delay kidney aging by suppressing DNA damage and the SASP. These findings provide key insights into the pathophysiology of kidney aging and clues to a novel intervention that might prevent age-related kidney disease and maintain kidney health. Funding: Commercial Support - Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology and Osaka Kidney Bank, Government Support - Non-U.S.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.