Ischemia reperfusion injury (IRI) is a major source of morbidity in renal transplantation (Tx), as well as after cardiac arrest, cardiopulmonary bypass, and trauma. IRI and related early allograft dysfunction occur in ~30% of renal Tx recipients and are associated with poorer long-term outcomes. Kidney scarcity has also led to acceptance of grafts with greater degrees of baseline ischemic insult. These factors help explain why short-term graft survival has steadily improved in conjunction with the development of better immunosuppression but why long-term graft survival has been unchanged for nearly 2 decades. Our central goal is to develop ways to limit renal IRI and preserve renal function following renal Tx and other clinical scenarios. This proposal builds on our work in murine models showing that estrogen therapy preserves renal function and mitigates development of fibrosis after warm or cold renal IRI. We found that estrogen’s actions via estrogen receptor-alpha (ER) are renal-extrinsic, whereas actions of estrogen receptor-beta (ER) may diminish the benefits of estrogen therapy on renal IRI and are renal-intrinsic. We plan to further explore these actions, with an eye to improving clinical outcomes. Aim 1. Assess the cells/tissues responsible for the differential effects of ER and ER on renal IRI. Whole animal ER deletion leads to decreased renal IRI tolerance, and in Tx experiments, renal ER deletion does not impact IRI tolerance whereas deletion in the recipient dramatically worsens IRI. In contrast, whole animal ER deletion leads to increased renal IRI tolerance, and in Tx experiments, ER deletion in the renal Tx promotes IRI tolerance whereas deletion in the recipient has no benefit on IRI. Using cellular, biochemical, and transcriptomic studies, we will assess various cell lineages for their contribution to the opposite effects of 1.1) ER and 1.2) ER deletion on renal IRI. Aim 2. Probe the utility of SERMs and related compounds to modulate outcomes of renal IRI. We have tested various SERMs for their impact on IRI in mice and shown that raloxifene, a clinically approved osteoporosis drug, is superior to estrogen in promoting renal protection, while several other SERMs have no impact on renal IRI. Using murine models of renal IRI we will test whether: 2.1) ER antagonists, or 2.2) a SERM, such as raloxifene, in combination with an ER antagonist can maximize beneficial effects against renal IRI. Our studies will identify pathogenetic mechanisms and test new approaches to prevent acute and chronic kidney injury with significant potential for translational intervention.