Abstract: SA-PO1109
Sexual Dimorphism in Kidney Aging: Estrogen and Adenosine Coordinate Tubular-Macrophage Cross-Talk via Lipid Metabolism
Session Information
- Geriatric Nephrology
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Geriatric Nephrology
- 1300 Geriatric Nephrology
Authors
- Qi, Hao, Xiangya Hospital Central South University, Changsha, Hunan, China
- Xie, Tingting, Xiangya Hospital Central South University, Changsha, Hunan, China
- Chen, Changhan, Xiangya Hospital Central South University, Changsha, Hunan, China
- Kellems, Rodney Eugene, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, Texas, United States
- Xia, Yang, Xiangya Hospital Central South University, Changsha, Hunan, China
Background
Metabolic dysregulation and chronic inflammation synergistically contribute to renal aging, which exhibits pronounced sexual dimorphism. However, the mechanisms remain poorly understood. This study aims to investigate the metabolic underpinnings of gender-dependent renal aging.
Methods
Renal tissues from male and female mice aged 1, 2, 10, and 16 months were subjected to histopathological examination and immunohistochemical staining. Metabolic alterations were analyzed using untargeted metabolomics. To validate the metabolomic findings, we employed three distinct mouse models: (1) ovariectomized mice (2 months old), (2) L-carnitine supplementation (10 months old), and (3) macrophage-specific Adora2b receptor(A2bR) knockout mice with kidney disease.
Results
Phenotypically, male mice exhibited accelerated renal aging marked by exacerbated tubular atrophy, interstitial fibrosis, and macrophage infiltration. Untargeted metabolic screening uncovered sex differences: aged males showed severe of fatty acid accumulation, L-carnitine depletion, and reduction of adenosine than females. Gene profiling identified females maintained higher fatty acid β-oxidation genes expression, with reduced lipid droplets ectopic deposition. Estrogen supplementation significantly alleviated ovariectomy-induced renal lipid accumulation and macrophage infiltration. Similarly, L-carnitine supplementation attenuated ectopic lipid droplet deposition and inflammatory responses, confirming that boosting fatty acid catabolism mitigates aging-related pathology. As for adenosine change, macrophage-specific adenosine A2b receptor (A2bR) deletion accelerated kidney disease progression, and in vitro studies revealed that A2bR deficiency amplified palmitate-triggered inflammatory responses, demonstrating that A2B receptor activation suppresses lipotoxicity-driven macrophage inflammation.
Conclusion
Our findings demonstrate that sex-dimorphic renal aging stems from divergent lipid metabolism and inflammatory crosstalk. Estrogen enhances fatty acid β-oxidation in epithelial tubular cells, reducing ectopic lipid deposition, while adenosine-A2B receptor signaling in macrophages suppresses lipotoxicity-induced inflammation and fibrosis. This study provides a mechanistic link between ectopic lipid deposition and age-related multi-organ decline.
Funding
- Government Support – Non-U.S.