Beyond UPR: cell-specific roles of ER stress sensor IRE1a in kidney ischemic injury and transplant rejection

Kidney damage due to ischemia or rejection results in the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER) lumen, a condition known as ER stress. Inositol-requiring enzyme 1a (IRE1a), the first ER stress sensor found, is a type I transmembrane protein with kinase and endoribonuclease activity. On activation, IRE1a nonconventionally splices an intron from unspliced X-box-binding protein 1 (XBP1) mRNA to produce XBP1s mRNA that encodes the transcription factor, XBP1s, for the expression of genes encoding proteins that mediate the unfolded protein response. The unfolded protein response promotes the functional fidelity of ER and is required for secretory cells to sustain protein folding and secretory capability. Prolonged ER stress can lead to apoptosis, which may result in detrimental repercussions to organ health and has been implicated in the pathogenesis and progression of kidney diseases. The IRE1a-XBP1 signaling acts as a major arm of unfolded protein response and is involved in regulating autophagy, cell differentiation, and cell death. IRE1a also interacts with activator protein-1 and nuclear factor-kB pathways to regulate inflammatory responses. Studies using transgenic mouse models highlight that the roles of IRE1a differ depending on cell type and disease setting. This review covers these cell specific roles of IRE1a signaling and the potential for therapeutic targeting of this pathway in the context of ischemia and rejection affecting the kidneys.

Automated summary

Kidney damage due to ischemia or rejection leads to ER stress and accumulation of unfolded and misfolded proteins. The IRE1a signaling pathway plays a crucial role in the unfolded protein response and is involved in regulating autophagy, cell differentiation, and cell death. The roles of IRE1a vary depending on cell type and disease setting.