The protective role of the IRE1α/XBP1 signaling cascade in autophagy during ischemic stress and acute kidney injury
Ting Liu, Lu Li, Meixia Meng, Ming Gao, Jinhua Zhang, Yuan Zhang, Yukun Gan, Yangjie Dang, Limin Liu
Abstract
Acute kidney injury (AKI) is a common and serious complication resulting from ischemia and hypoxia, leading to significant morbidity and mortality. Autophagy, a cellular process for degrading damaged components, plays a crucial role in kidney protection. The unfolded protein response pathway, particularly the inositol-requiring enzyme 1 (IRE1α)/X-box binding protein 1 (XBP1) signaling cascade, is implicated in regulating autophagy during renal stress. To elucidate the role of the IRE1α/XBP1 pathway in autophagy during hypoxia/reoxygenation (H/R) and ischemia/reperfusion (I/R) injury, renal tubular epithelial cells (TECs) were subjected to H/R conditions, and I/R injury was induced in mice. The expression of autophagy-related and endoplasmic reticulum stress markers (IRE1α, XBP1, GRP78, Beclin1, LC3I/II, and P62) was assessed using immunoblotting and immunofluorescence. Additionally, the impacts of IRE1α overexpression and pharmacological agents, IXA6 (IRE1α agonist), and STF083010 (IRE1α inhibitor) were evaluated on autophagy regulation. H/R injury significantly increased mitochondrial damage and the formation of autophagic vesicles in TECs. Key markers of autophagy were elevated in response to H/R and I/R injury, with activation of the IRE1α/XBP1 pathway enhancing autophagic processes. IXA6 treatment improved renal function and reduced injury in I/R models, while STF083010 exacerbated kidney damage. The IRE1α/XBP1 pathway is a critical regulator of autophagy in renal TECs during ischemic stress, suggesting that pharmacological modulation of this pathway may offer therapeutic avenues for preventing or mitigating AKI. Enhanced understanding of these mechanisms may lead to novel strategies for kidney disease management. • Inositol-requiring enzyme 1/X-box binding protein 1 signaling enhances autophagy during ischemic kidney injury. • Autophagy protects renal tubular epithelial cells from ischemia stress. • IXA6 improves kidney function; STF083010 worsens damage in ischemia/reperfusion models. • Targeting inositol-requiring enzyme 1/X-box binding protein 1 may provide new strategies against acute kidney injury. • Study reveals potential for new therapies in kidney disease management.