Abstract: FR-OR124
Modulation of Ischemia-Reperfusion Injury (IRI) Post-Renal Transplantation in Estrogen Receptor-α Knockout (ERα-KO) Mice and by Selective Estrogen Receptor Modulators (SERM)
Session Information
- Transplantation: Basic Research
November 08, 2019 | Location: 150, Walter E. Washington Convention Center
Abstract Time: 05:06 PM - 05:18 PM
Category: Transplantation
- 1901 Transplantation: Basic
Authors
- Hernandez, Paul T., Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Concors, Seth, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Wang, Zhonglin, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Ge, Guanghui, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Aufhauser, David Dean, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Krumeich, Lauren, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Hancock, Wayne W., Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Levine, Matthew H., Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background
IRI is a major contributor to early allograft dysfunction(EAD) post-kidney transplantation. We have demonstrated lower rates of EAD among female renal transplant recipients in UNOS, and using a murine model, showed improved IRI tolerance after administration of 17β-estradiol in both warm and cold renal IRI. We now investigate the contribution of ERα to this protection, and the utility of SERM administration in wild type mice.
Methods
Female C57BL/6(B6) and ERα-KO mice were used. We transplanted kidneys from B6→B6, ERα-KO→B6, and B6→ERα-KO, followed by native nephrectomy. All groups were treated with 17β-estradiol(1 mg/kg) and subsequently underwent temperature-controlled IRI(28min at 36°C). In a separate experiment, B6 mice received either Lasofoxifene(LAS), Raloxifene(RAL), Tamoxifen(TAM), Bazedoxifene(BAZ), or vehicle (all 10mg/kg in DMSO) prior to warm IRI. Serum creatinine(Cr) was measured at 24-hour intervals post-surgery in both experiments.
Results
Mice in the B6→ERα-KO group had significantly higher Cr compared to B6→B6 and ERαKO→B6 groups(Figure 1a). Mice treated with LAS prior to IRI had significantly lower Cr compared to controls(Figure 1b). RAL, TAM, or BAZ did not provide significant protection(Figure 1c).
Conclusion
Loss of estrogen-derived protection from warm IRI in the B6→ERα-KO group indicates that the mechanism for this protection is extrinsic to the kidney. Protection from IRI in the LAS-treated group demonstrates that selective ERα activation outside the breast and uterus, potentially sparing off-target effects, is sufficient for protection from IRI. Lack of significant protection from IRI after RAL, TAM, and BAZ is likely due to differential affinity of each drug for ERα in extra-renal tissues. Collectively, these data provide new insights into the mechanisms by which estrogen-based therapy can improve early outcomes in renal transplantation.
Funding
- NIDDK Support