Abstract: TH-PO0227
Hematopoietic Mosaic UTY Deficiency on the Y Chromosome Worsens Kidney Failure in Experimental Mice Model
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Arai, Yohei, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
- 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
- Doviak, Heather, University of Virginia School of Medicine, Charlottesville, Virginia, United States
- Walsh, Kenneth, University of Virginia School of Medicine, Charlottesville, Virginia, United States
Background
Chronic kidney disease (CKD) is a common condition affecting millions of people worldwide, with a higher incidence observed in male than in female. However, the mechanisms underlying this sex difference remain largely unclear. Our previous study demonstrated that hematopoietic mosaic loss of the Y chromosome (mLOY) is causally linked to an increased risk of renal fibrosis and kidney senescence. In the current study, we further identified the ubiquitously transcribed tetratricopeptide repeat gene, Y-linked (UTY), as a key factor responsible for the development of CKD in male mice with mLOY.
Methods
A mouse model of hematopoietic mosaic UTY-deficiency was employed to investigate whether a causal connection exists between hematopoietic UTY-deficiency and CKD. We evaluated the renal phenotypes in PepBoy (C57BL6/J congenic, CD45.1+) mice that had been transplanted with CD45.2+ bone marrow cells from UTY-deficient mice versus control wild-type (WT) mice. Upon naturally aging or pharmacological induction of kidney injury for CKD, hematopoietic mosaic UTY-deficiency and WT mice were evaluated renal phenotypes. To assess mechanistic aspects of CKD, RNA-sequencing were performed using kidney tissues collected from hematopoietic mosaic UTY-deficiency and WT mice.
Results
Hematopoietic mosaic UTY-deficiency causally led to renal dysfunction that was accompanied by senescent cell accumulation in murine models of advanced age and kidney injury. The analysis of transcriptional signatures in kidneys identified associations between immune cell UTY-deficiency and the accumulation of senescent cells, especially in proximal tubules. In aged hematopoietic mosaic UTY-deficiency mice, treatment with a senolytic agent suppressed the progression of renal dysfunction and fibrosis.
Conclusion
Disruption of the epigenetic regulator locus of UTY in hematopoietic cells recapitulates the aging phenotypes associated with Y chromosome loss in kidney disease.
Funding
- Government Support – Non-U.S.