Unraveling the cooperative action of p53 and autophagy against kidney aging

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K16163
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Osaka University
• Principal Investigator: Yamamoto Takeshi 大阪大学, 大学院医学系研究科, 特任助教(常勤) (20756994)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: p53 / オートファジー / DNA損傷 / がん / 腎障害

Outline of Final Research Achievements

Recently the diverse and global functions of p53 in the kidney under disease pathogenesis has been studied; however, its pathophysiological role in kidney aging remains uncertain. Using proximal tubular epithelial cell (PTEC)-specific p53 and/or atg5-deficient (p53 or atg5-TSKO) mice, we investigated the role of p53 and a possible interplay in the aged kidney and assessed the phenotypes of TSDKO mice at 24 months. p53-TSKO at 24 months exhibited DNA damage, thereby upregulating autophagy. On the other hand, aged atg5-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. Autophagy suppressed the SASP by degrading cytoplasmic chromatin fragments (CCFs) in aged kidneys. In conclusion, p53 and autophagy cooperatively delay kidney aging by suppressing DNA damage and the SASP.

Free Research Field

腎臓内科学

Academic Significance and Societal Importance of the Research Achievements

高齢腎において、p53は損傷DNAの修復、一方で、オートファジーは細胞質に漏出した損傷DNA（CCFs）の除去を介して、協調的にcGAS-STING-SASP経路の抑制、腎炎症（3次リンパ組織TLT形成）の抑制に働くことが明らかとなった。p53が変異している高齢担癌患者において、腎障害の発症・進展を抑制するために、オートファジー活性を適切に維持する必要がある。