Inhibition of <scp>IRE1α</scp> Alleviates Renal Fibrosis and Downregulates <scp>M1</scp> Macrophage Activation via the p38 <scp>MAPK</scp> Pathway

The enhanced M1 macrophage activation and proportion significantly promote the progression of renal fibrosis in the unilateral ureteral obstruction (UUO) model, while the underlying mechanisms need to be further studied. Here, we examined whether or not endoplasmic reticulum (ER) stress contributed to M1 macrophage activation and the mechanisms in this process. In the UUO mouse model, the proportion of M1 macrophages could be significantly increased in the early renal fibrosis, with the ER stress activated. The inhibitor of ER stress (4-PBA) significantly suppressed the activation of M1 macrophages and alleviated the renal fibrosis in the UUO mouse model. Furthermore, the renal fibrosis could be relieved after the administration of IRE1α inhibitor (4μ8C), with the downregulation of ER stress and M1 macrophage activation. Mechanistically, ER stress-enhanced activation of M1 macrophages was regulated through the IRE1α/XBP1s-p38 MAPK pathway. IRE1α-deficient macrophages could alleviate the renal fibrosis in the UUO mouse model. Thus, our findings suggest that the ER stress pathway regulates M1 macrophage activation in the UUO model, which provides a novel therapeutic approach for renal fibrosis.