Kidney Week

Abstract: FR-PO1233

Uncovering Deep Senescence in Failed-Repair Proximal Tubules via a Novel Genetic Mouse Model

Session Information

• CKD: Mechanisms, AKI, and Beyond - 2
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Yamada, Ryo, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Ryo Yamada, MD

• Morinishi, Takuya, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Takuya Morinishi, MD

• Iwashige, Yohei, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Yohei Iwashige, MD

• Muro, Koji, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Koji Muro, MD

• Yamamoto, Shigenori, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Shigenori Yamamoto, MD

• Morita, Keisuke, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Keisuke Morita, MD

• Konishi, Ryo, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Ryo Konishi

• Kitamura, Toshio, Foundation of Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan

Toshio Kitamura, MD, PhD

• Yanagita, Motoko, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Motoko Yanagita, MD, PhD

Group or Team Name

• Cell Cycle & Cellular Senescence Group.

Background

Cellular senescence, characterized by cell cycle arrest and secretory phenotypes, has attracted attention as a potential target for the treatment of age-related diseases. Although recent studies have suggested that cellular senescence may contribute to the pathogenesis of kidney diseases, its significance remains unclear. Furthermore, the potential role of senolytic treatments in this context is still under investigation.

Methods

We utilized transgenic mice that specifically expressed G0 marker in proximal tubular cells (PTCs) (G0 marker mice) and induced aristolochic acid- and cisplatin-induced nephropathies. Additionally, we evaluated the efficacy of senolytic treatment with ABT-263, a novel Bcl2 inhibitor, in an aristolochic acid nephropathy model.

Results

Utilizing G0 marker mice, we identified a subpopulation of G0 positive proximal tubular cells (PTCs) with strong Cyclin D1 expression (G0-double positive cells: G0^DP cells). G0^DP cells exhibited various features of cellular senescence, including nuclear abnormalities and accumulation of DNA damage foci. G0^DP cells resided exclusively within failed-repair PTCs (FR-PTCs), which have recently attracted attention for their proinflammatory phenotypes. The number of G0^DP cells among the FR-PTCs differed depending on the kidney injury model, time after injury, and severity of injury. Spatial transcriptomic analysis revealed more senescent phenotypes in G0^DP cells among FR-PTCs, and identified transcription factors activated in G0^DP cells, such as Trp53, NF-κB, RUNX1, and STAT1. Senolytic treatment using ABT-263 significantly reduced FR-PTCs, but failed to deplete G0^DP cells or improve kidney function.

Conclusion

G0^DP cells exhibit prominent features of cellular senescence, and comprised a subpopulation of FR-PTCs. Conventional senolytic treatment may be insufficient to improve kidney function because of the resistance of G0^DP cells.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025fcvy2azt