Abstract: FR-OR071
Differential Effects of Estrogen Receptor (ER)-alpha and ER-beta on Female Tolerance of Kidney Ischemia-Reperfusion Injury
Session Information
- Transplantation: Basic Science Innovations and Advances
November 07, 2025 | Location: Room 370A, Convention Center
Abstract Time: 05:40 PM - 05:50 PM
Category: Transplantation
- 2101 Transplantation: Basic
Authors
- Levine, Matthew H., University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Christensen, Lanette M, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Wang, Zhonglin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Ge, Guanghui, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Hancock, Wayne W., The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
Background
Ischemia/reperfusion injury (IRI) is a common cause of delayed graft function in kidney transplant (Tx) recipients. Clinically and experimentally, females display greater tolerance than males to IRI and have improved outcomes post-Tx. Moreover, treatment with exogenous estradiol improves protection against renal IRI in female mice. To further investigate the mechanisms responsible, estrogen receptors alpha (ERα) and beta (ERβ) were evaluated for their roles in renal IRI.
Methods
Renal allo- or iso-grafting was performed followed by native nephrectomy and 28 min warm IRI of the kidney Tx, using ERα-/- or ERβ-/- mice as renal donors and/or recipients, with B6 (WT) controls. Kidney function was evaluated by serial blood urea nitrogen (BUN) and serum creatinine (SC) levels.
Results
Engraftment of female WT kidneys into ERα-/- mice severely impaired renal function, while female ERα-/- kidney Tx into WT was protective, as displayed by BUN (p<0.05) and SC (p<0.05). Together with previously published data showing that global lack of ERα greatly impairs kidney function post-IRI (p<0.05), these results indicate the importance of renal-extrinsic ERα for IRI tolerance. Consistent with this, IRI tolerance was enhanced in mice with deletion of ERα primarily in renal tissue using ERα-/-Pax8cre, having reduced BUN (p<0.01) and SC (p<0.001). In contrast, absence of ERβ was protective following IRI, having reduced BUN (p<0.01) and SC (p<0.01). Engraftment experiments with ERβ-/- and WT mice showed that the beneficial effects of ERβ deletion were renal-intrinsic, whereby Tx of ERβ-/- kidneys into WT mice was protective while WT kidneys into ERβ-/- mice enhanced renal IRI as shown by BUN (p<0.05) and SC (p<0.05). Reduction of CD8 expression within ERβ-/- kidneys (p<0.05) suggests immune involvement in the renal-intrinsic IRI protection by ERβ deletion. Given the contrasting effects of ERα-/- versus ERβ-/- deletion, the effects of dual ERα/ERβ deletion were tested. ERα had the dominant phenotype, such that levels of BUN and SC post-IRI did not differ between ERα-/- and ERα-/-/ERβ-/- mice.
Conclusion
ERα and ERβ affect renal IRI tolerance in females, with ERα displaying a dominant phenotype. These results highlight the possible therapeutic applications of targeting ERα post-Tx, in addition to pre-treatment ERβ-targeting of donors.
Funding
- Other NIH Support