*Purpose: Renal Ischemia Reperfusion Injury (IRI) is a major contributor to delayed graft function (DGF) in kidney transplantation. Previously, we have shown lower rates of DGF among female renal transplant recipients in the UNOS registry, and using a murine model, we demonstrated improved IRI tolerance with administration of supplemental 17β-estradiol (E2) and selective estrogen receptor modulators (SERM). There are two principal estrogen receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), and expression varies by tissue type. We have shown decreased ischemia tolerance in ERα knockout mice (ERα-KO). Given the therapeutic potential of manipulating the estrogen receptors with E2 or SERM, understanding the role of the ERβ in renal IRI is essential.

*Methods: Female Erβ-KO mice and ERαβ-KO mice underwent warm renal ischemia along with B6 controls. Renal ischemia was repeated with ERαβ-KO and ERα-KO mice using a shortened ischemic time. Additionally, we transplanted kidneys from C57BL/6(B6) donor mice into B6 recipient mice, ERβKO kidneys into B6 recipients, and B6 kidneys into ERβKO recipients, followed by native nephrectomy. All groups subsequently underwent standardized renal IRI. 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 1a). 5 of 7 ERαβ-KO mice undergoing standard IRI experienced fatal renal injury, as compared to zero controls, with ERαβ-KO mice having significantly higher BUN (135 +/-14) than B6 controls (104 +/-13, p=0.003) at 24 hours. In modified IRI, ERαβ-KO had no difference from ERα-KO mice (Figure 1b). ERβ-KO mice that received B6 kidneys (B6=>ERβKO) had significantly higher BUN and Cr compared to B6 mice that received ERβKO kidneys (ErβKO=>B6) (p<0.001) and significantly higher Cr than B6 mice that received B6 kidneys (B6=>B6) (p <0.05, Figure 1c).

*Conclusions: ERβ-KO is protective against renal IRI, but combined deletion of ERα and ERβ recapitulates the previously shown harmful effects of ERα deletion. The protective effect of ERβ deletion appears to be localized to the kidney. Differential blockade of ERα and Erβ in the kidneys vs. the periphery may provide an avenue to increase the protective effects of estrogen in renal IRI.

« Back to 2021 American Transplant Congress