Kidney Week

Abstract: FR-PO1230

Kidney Aging Mediated by PRDM16 Deficiency Driving Multiple Organ Aging

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

• Yuan, Qian, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China

Qian Yuan, PhD

• Ma, Sijia, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China

Sijia Ma

• Zhang, Chun, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China

Chun Zhang, MD, PhD

Background

Organ aging constitutes a critical determinant in the pathogenesis of age-related chronic diseases, imposing a substantial burden on global public health. As the pivotal regulatory organ for systemic metabolic homeostasis, the kidney's potential role as a central orchestrator of organism-wide aging processes remains undefined. Our prior research identified PR domain-containing 16 (PRDM16) as a critical modulator of renal aging; however, its potential involvement in renal-driven systemic aging and the underlying mechanisms remain unclear.

Methods

To delineate the impact of PRDM16 deficiency in renal tubular epithelial cells on organism-wide aging, we constructed aging animal models including radiation-accelerated renal aging model (8-week post-exposure) and naturally aging model (18-months) with tubular-specific PRDM16 knockout mice (Cre⁺/Prdm16^flox/flox) and control littermates (Cre^-/Prdm16^flox/flox), supplemented by multi-organ aging mapping through various morphological and senescent burden quantification. In vitro, HK2 cells with lentiviral-mediated PRDM16 overexpression or siRNA-directed knockdown were engineered to delineate corresponding mechanisms.

Results

Tubular-specific knockout of PRDM16 exacerbates multi-organ aging in aging animal models, manifesting as pituitary somatotroph granule depletion, femoral trabecular bone loss, gonadal atrophy, myocardial hypertrophy, histopathological aberrations of organs like liver, skin, lung, and the accumulation of senescent cells. Mechanistically, PRDM16 functions as a transcriptional activator of klotho, and knockdown of klotho abolished PRDM16-dependent anti-aging effects in vitro. Furthermore, PRDM16 orchestrates transcriptionally active H3K4me3 epigenetic marks, which binds to the klotho promoter to drive its transcriptional activation.

Conclusion

Renal aging emerges as a pivotal driver of organism-wide aging. PRDM16 deficiency in renal tubular epithelial cells aggravates systemic aging through H3K4me3 hypomethylation-driven transcriptional suppression of klotho, establishing a novel epigenetic axis connecting renal aging with organism-wide aging processes.

Funding

• Government Support – Non-U.S.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20252acxk0x9