The Selective Estrogen Receptor Modulator, Raloxifene, Is Protective Against Renal Ischemia-reperfusion Injury

Abstract

Background: There is increasing evidence that estrogen is responsible for improved outcomes in female kidney transplant recipients. Although the exact mechanism is not yet known, estrogen appears to exert its protective effects by ameliorating ischemia-reperfusion injury (IRI). In this study, we have examined whether the beneficial effects of exogenous estrogen in renal IRI are replicated by therapy with any one of several selective estrogen receptor modulators.

Methods: C57BL/6 adult mice underwent standardized warm renal ischemia for 28 min after being injected with the selective estrogen receptor modulators, raloxifene, lasofoxifene, tamoxifen, bazedoxifene, or control vehicle (dimethyl sulfoxide), at 16 and 1 h before IRI. Plasma concentrations of blood urea nitrogen and creatinine were assessed 24, 48, 72, and 96 h post-IRI. Tissue was collected 30 d postischemia for fibrosis analysis using Sirius Red staining.

Results: Raloxifene treatment in female mice resulted in significantly lower blood urea nitrogen and creatinine after IRI and significantly lower fibrosis 30 d following IRI.

Conclusions: Raloxifene is protective against both acute kidney injury and fibrosis resulting from renal IRI in a mouse model.

FIGURE 1.

Female mice treated with raloxifene had significantly lower BUN (A) and creatinine (B) after IRI than controls; female mice treated with raloxifene had significantly less renal interstitial fibrosis at 30 d post-IRI by automated Sirius Red quantification (C). Representative images of Sirius Red staining of control (D and F) and raloxifene-treated animals (E and G) 30 d post-IRI. Male mice treated with raloxifene did not show a significant difference in BUN (H) or creatinine (I) post-IRI. Raloxifene did not meaningfully impact baseline BUN (J) or creatinine (K) levels in animals before IRI. BUN, blood urea nitrogen; IRI, ischemia–reperfusion injury.

FIGURE 2.

Female mice treated with lasofoxifene (A and B), tamoxifen (C and D), or bazedoxifene (E and F) did not show significantly less renal injury after warm IRI as measured by blood urea nitrogen or serum creatinine than controls. BUN, blood urea nitrogen; IRI, ischemia–reperfusion injury.

FIGURE 3.

Female mice treated with tamoxifen did not show significantly less renal interstitial fibrosis at 30 d post-IRI by automated Sirius Red quantification. IRI, ischemia–reperfusion injury.