#1240 Tamoxifen induces antioxidants to attenuate ischemia-reperfusion renal injury

Abstract Background and Aims The incidence of acute kidney injury (AKI) is increasing, posing a significant burden on global morbidity and mortality rates. Additionally, AKI serves as a critical risk factor for the development of chronic kidney disease (CKD), with both conditions contributing to substantial healthcare costs worldwide. Despite these pressing challenges, there are currently no effective therapeutic agents available in clinical practice to prevent AKI, lessen its severity, or promote renal recovery. Notably, our research has demonstrated that tamoxifen (TAM), a well-established and widely utilized selective estrogen receptor modulator for breast cancer, exhibits significant protective effects in reducing the severity of AKI. Method The ischemia-reperfusion injury (IRI) model was used to study AKI. In the in vivo experiments, TAM was administered prior to AKI induction. Renal function was assessed, and the proliferation and apoptosis of tubular cells were analyzed. To gain deeper insights, we used the Translating Ribosome Affinity Purification (TRAP) method in conjunction with Pax8 rtTA;LC-1;EGFP-L10a triple-transgenic mice to isolate and sequence mRNA from tubular cells. Single-cell RNA sequencing was also conducted on mice with and without TAM treatment. Furthermore, the oxidative stress resistance capacity was evaluated in mouse renal proximal tubular epithelial cells (MRPTEpiC) treated with TAM. Results In the animal model of IRI-AKI, mice treated with TAM exhibited lower plasma levels of blood urea nitrogen and creatinine compared to the non-TAM group. TAM treatment also led to fewer apoptotic tubular cells and an increase in proliferative tubular cells. TRAP and single-cell RNA sequencing analyses revealed elevated gene expression of both oxidase-related and antioxidant factors in tubular cells following tamoxifen administration. Furthermore, in vitro experiments showed that TAM-treated MRPTEpiC cells had an enhanced oxygen radical absorbance capacity. Conclusion TAM shows promise in alleviating the severity of IRI-AKI by reducing tubular cell apoptosis. Preconditioning with TAM boosts antioxidative capacity in mice, significantly reducing the severity of subsequent IRI-AKI. These results highlight TAM's potential as a therapeutic agent for AKI prevention.