Transient DNA damage in early life programs proximal tubular plasticity: dual outcomes of vulnerability and resilience associated with cellular senescence

Aging-related decline in renal function exhibits substantial interindividual variability, which is partly driven by acquired DNA stress. DNA damage induces genomic instability and cellular senescence, contributing to renal fibrosis and metabolic disorders. We previously demonstrated that genomic instability aggravates renal outcomes in human and experimental models (Kishi S et al., JCI, 2019; Sci Transl Med, 2019; BBRC, 2022). However, the long-term consequences of transient DNA damage in early life, particularly its potential to establish a “damage memory” in proximal tubular cells, remain unclear. This study aimed to elucidate how transient DNA double-strand breaks (DSBs) affect renal aging processes, metabolic phenotypes, and context-dependent adaptive responses.

Tamoxifen-inducible ICE (Induced Changes in the Epigenome) mice were generated by crossing I-PpoISTOP/+ and CreERT2/+ strains. Upon tamoxifen (tm) administration, the endonuclease I-PpoI induces non-mutagenic DSBs at 15 specific genomic motifs, which are subsequently repaired without mutational accumulation. ICE mice were treated with tm at 4 months (ICE_tm⁺) and analyzed at 7 and 14 months.

Single-nucleus RNA sequencing (snRNA-seq) was performed to profile cell populations and transcriptional changes in kidneys, focusing on proximal tubules and fibroblast subsets. Expression of senescence- and repair-related genes (Cdkn1a/p21, Mgmt) was validated.

To assess systemic consequences, proximal tubule–specific PTEC-ICE mice were subjected to (1) combined metabolic stress (hyperglycemia, high-fat diet, and high-salt water) and (2) repeated low-dose cisplatin exposure.

1. Persistent fibrotic remodeling and damage memory

In ICE_tm⁺ mice, snRNA-seq at 7 months revealed a reduction in S1–S2 proximal tubular cells with a concomitant increase in fibroblasts. By 14 months, glomerulosclerosis and interstitial fibrosis were exacerbated. Expression of Cdkn1a (p21) and Mgmt remained elevated, suggesting long-term transcriptional memory of DNA damage. VCAM1⁺ incompletely repaired tubules were more abundant in older ICE_tm⁺ kidneys.

 2. Metabolic vulnerability under systemic stress

In the PTEC-ICE_tm⁺ metabolic stress model, albuminuria, urinary KIM-1, hyperglycemia, and elevated liver enzymes were observed at 8 months, despite similar baseline glycemia. These findings indicate that transient early-life DNA damage disrupts proximal tubular metabolic homeostasis, promoting systemic metabolic vulnerability.

 3. Context-dependent protective response

In contrast, repeated low-dose cisplatin treatment in PTEC-ICE_tm⁺ mice attenuated renal dysfunction, as evidenced by reduced BUN elevation. Although fibrosis-related gene expression changes were modest, these results imply priming of DNA repair and stress response pathways, including MGMT, resembling an epigenetic preconditioning-like effect. Thus, early-life DNA damage may establish a plastic program balancing susceptibility and resilience.

Transient DNA damage during early life imprints a long-lasting molecular memory within proximal tubular cells, leading to sustained alterations in renal and systemic metabolism. While this memory predisposes to fibrosis and metabolic deterioration under stress, it can also promote adaptive resistance to subsequent injury. These findings identify DNA damage as a plastic determinant that may either accelerate or modulate renal aging, highlighting its dual role as a driver and regulator of age-related pathology. Further mechanistic and translational studies are warranted to validate this concept in humans.