Abstract: SA-PO0273
Androgens Promote Male-Specific SOX9 Upregulation in Injured Proximal Tubules
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
- Vermillion Allison, Corynne Reahna, The Ohio State University, Columbus, Ohio, United States
- Bajwa, Amandeep, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
- Pabla, Navjot, The Ohio State University, Columbus, Ohio, United States
- Kim, Jiyoung, The Ohio State University, Columbus, Ohio, United States
Background
Biological sex influences susceptibility, repair, and long-term outcomes following acute kidney injury (AKI); however, most mechanistic studies in rodent models have been performed in males with limited evaluation of whether injury responses are conserved in females. SOX9 is a key injury-induced transcription factor in proximal tubular cells that promotes adaptive repair during the acute phase of AKI while contributing to maladaptive remodeling during chronic injury. Given its established developmental role in sex determination and emerging importance in tubular injury responses, we investigated whether SOX9 mediates sex-specific repair programs in the adult kidney.
Methods
Ischemia-reperfusion and cisplatin injury conditions were optimized to generate injury-matched AKI models in male and female mice. These models were used to determine whether proximal tubular injury responses, particularly Sox9 induction, differ between sexes. Tubule-specific knockout mice for Sox9, Sox4, Sox11, Vgf, Zfp24, and the androgen receptor (Ar), together with gonadectomy, testosterone replacement, and molecular analyses, were used to define the regulatory mechanisms controlling sex-dependent tubular responses.
Results
Under injury-matched conditions, canonical injury markers including NGAL and KIM1 were comparably induced in both sexes; however, Sox9 and its downstream effector Vgf exhibited markedly reduced induction in females. Tubule-specific deletion of Sox9, Zfp24, or Vgf exacerbated kidney injury in males but had minimal effects in females. In contrast, Sox4 and Sox11 were similarly induced and functionally protective in both sexes. Castration or proximal tubule-specific deletion of Ar abolished injury-induced Sox9 upregulation in males, whereas testosterone replacement restored this response, establishing a testosterone-dependent signaling axis controlling male-specific SOX9 activation.
Conclusion
These studies identify a hormone-dependent, male-specific proximal tubular injury response mediated by androgen receptor signaling and SOX9 activation. The findings demonstrate that molecular pathways activated during kidney injury differ fundamentally between sexes despite equivalent degrees of tissue damage, highlighting the importance of incorporating sex-specific biology into therapeutic strategies for AKI.
Funding
- NIDDK Support