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Rapamycin, an immunosuppressant, is widely used in patients with kidney transplant. However, the therapeutic effects of rapamycin remain controversial. Additionally, previous studies have revealed deleterious effects of rapamycin predominantly when administered for =24 h. Few studies, however, have focused on the short-term effects of rapamycin administered only during the initial reperfusion phase. As such, we designed this study to explore the potential effects and mechanisms of rapamycin under a specific therapeutic regimen in which rapamycin is mixed in the perfusate during the initial reperfusion phase (within 24 h). Interestingly, we found that rapamycin maintained renal function and attenuated ischemia-reperfusion (I/R)-induced apoptosis in vivo and in vitro during the initial reperfusion phase, especially at 8 h after reperfusion. Simultaneously, rapamycin activated autophagy and inhibited endoplasmic reticulum (ER) stress and 3 pathways of unfolding protein response: ATF6, PERK, and IRE1a. Interestingly, we further found that the protective effects of rapamycin were suppressed when autophagy was inhibited by chloroquine and 3-methyladenine or when ER stress was induced by thapsigargin. Moreover, in terms of the regulatory effects of rapamycin, a negative-feedback loop between autophagy and ER stress occurred, with autophagy inhibiting ER stress and increased ER stress promoting autophagy during the initial reperfusion phase of renal I/R injury. Our study provides evidence that immediate reperfusion with rapamycin during the initial reperfusion phase repairs renal function and reduces apoptosis via activating autophagy, which could further inhibit ER stress. These results suggest a novel treatment modality for application during the initial reperfusion phase of renal I/R injury caused by kidney transplantation. [ABSTRACT FROM AUTHOR]