The IRE1 α -XBP1s-NF κ B axis controls cell survival and epithelial differentiation under osmotic stress through...

Arachidonic acid (AA) metabolism plays a critical role in renal cell osmoadaptation. We recently demonstrated that hypertonicity induces the expression and activation of cytosolic phospholipase A ${}_2$ (cPLA ${}_2$ ). On one hand, AA released by cPLA ${}_2$ enhances triacylglyceride (TG) synthesis and accumulation. On the other hand, AA is converted into prostaglandins (PG) through cyclooxygenase 2 (COX2) activity. Both processes are required for renal cell survival under osmotic stress. However, the mechanisms by which hypertonicity induces cPLA ${}_2$ expression remain poorly understood. Given that we previously shown that hypertonicity regulates TG synthesis through the IRE1 $\alpha$ -XBP1s branch of the unfolded protein response (UPR), here we examined whether XBP1s regulates the cPLA ${}_2$ -AA-COX2 axis in renal cells subjected to osmotic stress. We found that XBP1s modulates hypertonicity-induced expression of cPLA ${}_2$ and COX2 by increasing NF $\kappa$ B transcriptional activity. Inhibition of IRE1 $\alpha$ impaired normal COX2 degradation and disrupted AA metabolism, leading to a decrease in cell viability and preventing hypertonicity-induced epithelial differentiation. Prostaglandin E2 (PGE2) contributed to cell polarization facilitating adherens junction (AJ) assembly. Together, these findings highlight a central role for the IRE $\alpha$ -XBP1s-NF $\kappa$ B signaling axis in coordinating cell stress responses and epithelial differentiation through AA metabolism activation.