Kidney Week

Abstract: TH-PO1092

Transient DNA Damage in Proximal Tubules Accelerates Kidney Aging

Session Information

• CKD: Mechanisms - 1
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Takasu, Masanobu, Kawasaki Ika Daigaku, Kurashiki, Okayama, Japan

Masanobu Takasu, MD

• Kishi, Seiji, Kawasaki Ika Daigaku, Kurashiki, Okayama, Japan

Seiji Kishi, MD, PhD

• Kirita, Yuhei, Kyoto-fu, Kyoto, Kyoto, Japan

Yuhei Kirita, MD, PhD

• Kidokoro, Kengo, Kawasaki Ika Daigaku, Kurashiki, Okayama, Japan

Kengo Kidokoro, MD, PhD

• Sasaki, Tamaki, Kawasaki Ika Daigaku, Kurashiki, Okayama, Japan

Tamaki Sasaki, MD, PhD

• Kashihara, Naoki, Kawasaki Ika Daigaku, Kurashiki, Okayama, Japan

Naoki Kashihara, MD, PhD

• Hayano, Motoshi, Keio Gijuku Daigaku, Minato-ku, Tokyo, Japan

Motoshi Hayano, PhD

Background

As global aging, it is crucial to investigate how aging impacts organ functions. CKD is increasingly prevalent among older populations. Research shows that kidney function gradually declines until age 40, after which the deterioration accelerates (J Am Geriatr Soc, 1985; Nephrol Dial Transplant, 2006). This underscores the role of aging in elevating kidney disease risk. However, the reasons behind the rapid decline in kidney function post-40 and the impact of early adult lifestyle choices on later kidney health remain unclear. Our previous studies with ICE (Inducible Changes in Epigenome) mice (Hayano et al, Cell, 2023), motivate this investigation into how DNA stress contributes to kidney aging.

Methods

We developed ICE mice by crossing I-PpoI^STOP/+ mice with Cre^ERT2/+ mice. The enzyme I-PpoI only causes DNA double-strand breaks during tamoxifen administration, which are repaired via the DNA damage repair pathway. We fed 4 to 6 month-old ICE mice a tamoxifen-enriched diet for three weeks and euthanized them at 14 months. We then conducted a thorough examination of their kidney function, including histology, snRNA sequencing, qPCR, and WB analysis.

Results

Histological evaluation showed no significant changes in interstitial fibrosis between ICE and control mice. However, snRNA sequencing revealed an increase in the proximal tubules of ICE mice expressing Kim-1 and Vcam-1, markers of failed repair. Increased expression of VCAM-1 at the protein level was also confirmed by WB and immunostaining. We also observed heightened expression of p21 and upregulation of the DNA repair gene Mgmt, indicating genomic instability and progressive cellular senescence in the proximal tubules. Assessments of whole kidneys showed no changes in mitochondrial number, and single-cell analysis indicated no significant differences in mitochondrial function.

Conclusion

Our findings suggest that even brief, transient DNA damage, though repaired, can have long-term effects on kidney health, particularly in the proximal tubules. These tubules exhibit signs of DNA instability and accelerated cellular senescence, which may increase their vulnerability to external damage. This vulnerability underscores the susceptibility of the proximal tubules to DNA damage and could explain the diminished recovery from acute kidney injury observed in older individuals.