Abstract: SA-PO1201
Hematopoietic Mosaic Loss of Y Chromosome Promotes Renal Cell Senescence and Kidney Diseases
Session Information
- CKD: Mechanisms - 3
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Arai, Yohei, University of Virginia School of Medicine, Charlottesville, Virginia, United States
- Chavkin, Nicholas W., University of Virginia School of Medicine, Charlottesville, Virginia, United States
- Arai, Yuka, University of Virginia School of Medicine, Charlottesville, Virginia, United States
- Halvardson, Jonatan, Uppsala Universitet, Uppsala, Sweden
- Bjurling, Josefin, Uppsala Universitet, Uppsala, Sweden
- Doviak, Heather, University of Virginia School of Medicine, Charlottesville, Virginia, United States
- Forsberg, Lars A., Uppsala Universitet, Uppsala, Sweden
- Walsh, Kenneth, University of Virginia School of Medicine, Charlottesville, Virginia, United States
Background
Aging leads to the accumulation of senescent cells that, in turn, promote morbidity and mortality. Hematopoietic mosaic loss of Y chromosome (mLOY) with age is the most frequently acquired somatic mutation in males, and this condition has been associated with various age-associated diseases and reduced lifespan. The pathogenesis of kidney diseases is associated with the infiltration of immune cells in response to the kidney injury, and senescent cells accumulate in kidney in response to injury or advance age. However, the roles of hematopoietic mLOY in renal disease progression and senescent cell accumulation are unknown.
Methods
We investigated the association between the LOY percentage in leukocytes and the incidence of kidney diseases using male dataset derived from a prospective cohort study of a half million individuals with paired genetic and phenotype information. To assess the specific transcriptional signatures associated with hematopoietic mLOY, cross-sectional analyses were performed on a single-cell RNA sequencing dataset of renal biopsies from healthy control males and male patients with kidney diseases. A mouse model of hematopoietic mLOY was employed to examine whether hematopoietic mLOY is causally link to kidney diseases.
Results
A prospective cohort study (n=216,608) revealed an association between mLOY in blood and the incidence of kidney diseases during the follow-up period (median 14.8 years). The analysis of transcriptional signatures in human kidneys identified associations between disease progression, immune cell LOY and the accumulation of senescent cells. Hematopoietic mLOY causally led to renal dysfunction that was accompanied by senescent cell accumulation in murine models of advanced age and kidney injury. In aged mLOY mice, treatment with a senolytic agent suppressed the progression of renal dysfunction and prolonged lifespan.
Conclusion
Hematopoietic mLOY promotes renal cell senescence, contributing to the development of kidney disease. Senolysis could be a promising therapeutic strategy for hematopoietic mLOY.
Funding
- Other NIH Support