Estrogen Receptor Beta Deletion is Protective in Renal Ischemia Reperfusion Injury but Pharmacologic Inhibition of Estrogen Receptor Beta is Not
1Surgery, University of Pennsylvania, Philadelphia, PA, 2University of Pennsylvania, Philadelphia, PA, 3Childrens Hospital of Philadelphia, Philadelphia, PA
Meeting: 2022 American Transplant Congress
Abstract number: 677
Keywords: Ischemia, Kidney transplantation, Renal ischemia
Topic: Basic Science » Basic Science » 14 - Ischemia Reperfusion
Session Information
Session Time: 5:30pm-7:00pm
Presentation Time: 5:30pm-7:00pm
Location: Hynes Halls C & D
*Purpose: Renal Ischemia Reperfusion Injury (IRI) contributes substantially to delayed graft function (DGF) in kidney transplantation. Prior work by our group has shown lower rates of DGF among female renal transplant recipients in the UNOS registry, and in a murine model we have demonstrated improved IRI tolerance with administration of exogenous estrogen. There are two principal estrogen receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), and expression varies by tissue type, creating tissue specific responses to estrogen. We have shown decreased ischemia tolerance in ERα knockout mice. Here we interrogate the role of ERβ with both genetic knockouts and pharmacologic inhibition.
*Methods: Female Erβ-KO mice and C57BL/6 mice underwent warm renal ischemia, using a standardized technique with clamping of the renal pedicle for 28 minutes under strict temperature control, followed by contralateral nephrectomy. In another experiment C57BL/6 mice were given either PHTPP, an estrogen receptor antagonist with 36-fold specificity for the beta receptor or DMSO, 16 and 1 hours prior to ischemia. Blood urea nitrogen (BUN) and serum creatinine (Cr) were measured at 24-, 48-, 72- and 96-hours after IRI.
*Results: ERβ-KO mice had significantly lower BUN and Cr compared to B6 mice (p<0.001, Figure 1). PHTPP treated mice had no difference in BUN or creatinine (Figure 2).
*Conclusions: ERβ-KO is protective against renal IRI, but pharmacologic inhibition of ERβ does not recapitulate this protective effect. This suggests that the presence of the beta receptor, but not its stimulation with estrogen, is harmful in renal ischemia reperfusion injury. This may be due to the interactions of ERβ and the ERα with presence of beta receptors resulting in inhibition of beneficial estrogen alpha mediated effects. Further understanding of these pathways could lead to therapies to ameliorate renal ischemia reperfusion injury and delayed graft function.
To cite this abstract in AMA style:
OBrien C, Hernandez P, Concors S, Wang Z, Ge G, Hancock W, Levine M. Estrogen Receptor Beta Deletion is Protective in Renal Ischemia Reperfusion Injury but Pharmacologic Inhibition of Estrogen Receptor Beta is Not [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/estrogen-receptor-beta-deletion-is-protective-in-renal-ischemia-reperfusion-injury-but-pharmacologic-inhibition-of-estrogen-receptor-beta-is-not/. Accessed October 10, 2024.« Back to 2022 American Transplant Congress