In vivo analysis of cellular senescence in chronic kidney disease and renal cancer development

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17264
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: The University of Tokyo (2021-2022); Nippon Medical School (2020)
• Principal Investigator: Aratani Sae 東京大学, 医科学研究所, 助教 (60844131)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 慢性腎臓病 / 細胞老化 / 外的ストレス / DNA障害 / 活性酸素

Outline of Final Research Achievements

Previously, we generated a p16-CreERT2-tdTomato mouse model (p16-tdTomato mice hereafter) in which cells with high p16 expression, a prototypical senescent marker, were labeled with tdTomato through the administration of tamoxifen. We investigated different kidney conditions:normal aging kidneys, cisplatin-induced kidney diseases, rhabdomyolysis-induced kidney diseases, high-fat diet feeding model, adenine-induced kidney disease model. In the normal aging process, 20-24-month-old mice showed an accumulation in senescent cells compared to young mice. In kidney disease models, the senescent cells increased following CKD, particularly in proximal tubular epithelial cells (PTECs). RNA-sequence analysis revealed that senescent PTECs collected from the CKD model by FACS showed high inflammatory signaling pathways. These inflammatory cascades are all related to senescence-associated secretory phenotype. The senescent PTECs might be a therapeutic target to prevent CKD progression.

Free Research Field

腎臓内科

Academic Significance and Societal Importance of the Research Achievements

これまで細胞老化の研究は主に培養細胞の系で行われており、本研究は生体内の腎臓で様々な外的ストレスによって、老化細胞が誘導されることを観察し解析できた点にまず特色がある。腎臓において尿細管は最も広範囲を占めるが、様々なストレスにより、近位尿細管上皮細胞が最も細胞老化へと誘導されやすいことが分かった。さらに、このような尿細管の老化細胞は、慢性炎症の発症母地となる可能性が示唆された。このような慢性炎症を引き起こす老化細胞は今後の治療ターゲットになり得ることが考えられ、今後の治療薬開発に貢献する可能性を秘めており、本研究の成果は医療や産業へも貢献できるものと考えられた。