The IRE1 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="n002ea" overflow="scroll"> <mml:mi>α</mml:mi> </mml:math> -XBP1s-NF <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="n002ed" overflow=

Abstract 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 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="n004d4" overflow="scroll"> <mml:msub> <mml:mrow/> <mml:mrow> <mml:mn>2</mml:mn> </mml:mrow> </mml:msub> </mml:math> (cPLA <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="n004d7" overflow="scroll"> <mml:msub> <mml:mrow/> <mml:mrow> <mml:mn>2</mml:mn> </mml:mrow> </mml:msub> </mml:math> ). On one hand, AA released by cPLA <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="n004da" overflow="scroll"> <mml:msub> <mml:mrow/> <mml:mrow> <mml:mn>2</mml:mn> </mml:mrow> </mml:msub> </mml:math> 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 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="n004dd" overflow="scroll"> <mml:msub> <mml:mrow/> <mml:mrow> <mml:mn>2</mml:mn> </mml:mrow> </mml:msub> </mml:math> expression remain poorly understood. Given that we previously shown that hypertonicity regulates TG synthesis through the IRE1 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="n004e0" overflow="scroll"> <mml:mi>α</mml:mi> </mml:math> -XBP1s branch of the unfolded protein response (UPR), here we examined whether XBP1s regulates the cPLA <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="n004e3" overflow="scroll"> <mml:msub> <mml:mrow/> <mml:mrow> <mml:mn>2</mml:mn> </mml:mrow> </mml:msub> </mml:math> -AA-COX2 axis in renal cells subjected to osmotic stress. We found that XBP1s modulates hypertonicity-induced expression of cPLA <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="n004e6" overflow="scroll"> <mml:msub> <mml:mrow/> <mml:mrow> <mml:mn>2</mml:mn> </mml:mrow> </mml:msub> </mml:math> and COX2 by increasing NF <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="n004e9" overflow="scroll"> <mml:mi>κ</mml:mi> </mml:math> B transcriptional activity. Inhibition of IRE1 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="n004ec" overflow="scroll"> <mml:mi>α</mml:mi> </mml:math> 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 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="n004ef" overflow="scroll"> <mml:mi>α</mml:mi> </mml:math> -XBP1s-NF <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="n004f2" overflow="scroll"> <mml:mi>κ</mml:mi> </mml:math> B signaling axis in coordinating cell stress responses and epithelial differentiation through AA metabolism activation.