Kidney Week

Abstract: FR-PO0377

Highly Senescent Subpopulation of Failed Repair Proximal Tubular Cells Drives Kidney Injury Progression

Session Information

• AKI: Mechanisms - Metabolism and Repair
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

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

Ryo Yamada, MD

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

Koji Muro, MD

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

Yohei Iwashige, MD

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

Takuya Morinishi, 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

• Ikeda, Hiroyuki, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Hiroyuki Ikeda

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

Shinya Yamamoto, MD, PhD

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

Toshio Kitamura, MD, PhD

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

Motoko Yanagita, MD, PhD

Background

Cellular senescence, defined by the cessation of cell division and the adoption of secretory phenotypes in vitro, has been identified as a contributing factor to kidney injury progression; however, identification and characterization of senescent cells in vivo remain technically challenging. In particular, their relationship to failed repair proximal tubular cells (FR-PTC) is poorly understood.

Methods

We utilized proximal tubule-specific G0 reporter mice, which visualizes G0 phase proximal tubular cells (PTCs), and subjected them to kidney injury models and primary tubular cell culture. Additionally, we conducted region of interest (ROI)-targeted transcriptomics using a photo-isolation chemistry (PIC) method in an aristolochic acid nephropathy model. Furthermore, we assessed the therapeutic potential of ARV-825, a novel senolytic drug, in an aristolochic acid nephropathy model. Human kidney biopsy specimens were also analyzed.

Results

We identified that a distinct subpopulation of PTCs with both G0 marker and Cyclin D1 (G0^DP cells) exhibited significant senescent traits in both transcriptomic and proteomic levels following kidney injury. Primary culture analyses further confirmed the senescent traits of G0^DP cells. ROI-targeted spatial and molecular analyses demonstrated that G0^DP cells were localized within FR-PTCs, and represented the most senescent subpopulation among FR-PTC, while more than 90% of FR-PTCs were marked by G0 marker positivity. Treatment with ARV-825 selectively reduced the number of Cyclin D1-positive FR-PTCs, which predominantly corresponds to G0^DP cells, without affecting Cyclin D1-negative FR-PTCs in aristolochic acid nephropathy model. Treatment with ARV-825 further significantly improved serum creatinine levels and attenuated tubular injury, fibrosis and inflammation. In human kidney biopsy samples, Cyclin D1-positive FR-PTCs were predominantly found in patients with ATI/ATN and ANCA-GN, with their abundance correlating positively with lower eGFR and higher urinary β2-MG levels. These cells also expressed multiple cellular senescence markers.

Conclusion

Cyclin D1-positive FR-PTCs represent a highly senescent PTC subpopulation associated with kidney dysfunction. Selective elimination of these cells may represent a novel therapeutic strategy for kidney injury.