Negative feedback loop of autophagy and endoplasmic reticulum stress in rapamycin protection against renal ischemia‐reperfusion injury during initial reperfusion phase

Abstract

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 IRE1α. 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.-Li, X., Zhu, G., Gou, X., He, W., Yin, H., Yang, X., Li, J. Negative feedback loop of autophagy and endoplasmic reticulum stress in rapamycin protection against renal ischemia-reperfusion injury during initial reperfusion phase.

VEGF‐A promotes angiogenesis after acute myocardial infarction through increasing ROS production and enhancing ER stress‐mediated autophagy

“…They proposed a negative-feedback loop between autophagy and ER stress during the initial reperfusion phase of renal ischemiareperfusion injury (X. Li et al, 2018). Then what on earth the molecular mechanism of the interplay between ER stress and autophagy in VEGF-A-induced angiogenesis?…”

Endothelial protective effect of rapamycin against simulated ischemia injury through up-regulation of autophagy and inhibition of endoplasmic reticulum stress

“…Rapamycin, an immunosuppressive agent and mTOR inhibitor, exerts cytoprotective effects in both cell and animal models of ischemia [18,19]. The available data suggest that rapamycin activates protective autophagy and inhibits ER stress in ischemic neurons, hepatocytes and nephrons [20][21][22]. However, whether up-regulation of autophagy and attenuation of ER stress by rapamycin has a protective effect on ischemic ECs remains to be elucidated.…”

Pretreatment with Cholecalciferol Alleviates Renal Cellular Stress Response during Ischemia/Reperfusion-Induced Acute Kidney Injury

“…Recently, several reports indicate that renal ER stress is involved in the process of I/R-evoked AKI [8–10]. ER stress is mediated by three transmembrane ER-resident stress sensors including inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor (ATF6) [31].…”

“…According to a recent report, oxidative stress played important roles during I/R-evoked AKI [7]. On the other hand, several studies found that renal endoplasmic reticulum (ER) stress was involved in the pathogenesis of I/R-evoked AKI [8–10].…”