Abstract: SA-PO0280
The Androgen Receptor Is Dysregulated by Sex and Kidney Ischemia-Reperfusion Injury and Mediates Proximal Tubular Cell Dysfunction Under Hypoxia
Session Information
- AKI: Mechanisms - Cell Signaling
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Sarwar, Alisha, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
- Bozzo-Rey, Maya Gabrielle, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
- Xu, Riley, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
- McDonough, John Edward, Firestone Institute for Respiratory Health, St. Joseph’s Healthcare, Hamilton, Ontario, Canada
- Thorpe, Mackenzie I., Firestone Institute for Respiratory Health, St. Joseph’s Healthcare, Hamilton, Ontario, Canada
- Clotet Freixas, Sergi, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
Background
Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). In IRI, hypoxia impairs proximal tubular epithelial cell (PTEC) metabolism, driving inflammation and fibrosis. AKI severity is higher in males, suggesting male-related factors, such as the androgen receptor (AR), contribute to IRI pathogenesis. However, mechanisms underlying AR-mediated sex differences in IRI remain unclear. This study aims to investigates how AR expression and signaling contribute to sex differences in IRI outcomes.
Methods
Immunohistochemistry was performed on formalin-fixed paraffin-embedded kidney samples from male and female mice subjected to bilateral IRI or sham surgery. Human primary PTECs were exposed to normoxia or hypoxia for 12–16h with vehicle or physiological dose (3nM) of dihydrotestosterone (DHT), the primary AR ligand, with or without flutamide pre-treatment to inhibit AR.
Results
In a bilateral renal IRI mouse model, female mice were more resistant to kidney damage, whereas males showed greater increases in plasma creatinine and kidney injury molecule-1 (Fig 1A). Males also had greater renal AR expression than females, although IRI increased AR expression in both sexes (Fig 1B). In vitro, male and female PTECs expressed AR, with lower baseline expression in females. PTECs treated with DHT promoted AR translocation from the cytosol to the nucleus (Fig 2A). Under hypoxia, DHT increased AR expression, and lactate secretion without altering LDH release (cell death marker), indicating a hypoxia-driven glycolytic maladaptation (Fig 2B). DHT also enhanced of IL-6, IL-8, and CCL-2 secretion under hypoxia, an effect prevented by flutamide, an FDA-approved AR antagonist (Fig 2C).
Conclusion
These findings suggest sex differences in kidney IRI are associated with differential AR expression in vivo and in vitro. Moreover, the DHT-AR axis exacerbates hypoxic PTEC injury, posing AR as a potential driver and novel therapeutic target in IRI-induced AKI.
Figure 1. (A) Mice assesed 48h post-surgery. (B) Mice kidney stained for AR.
Figure 2. (A) Male PTECs ± DHT stained for AR. (B –C) Male PTECs after 12h hypoxia ± DHT ± 5 µM flutamide (FLUT).