Transcriptome changes in C57BL/6 mice after ischemia/reperfusion injury
Renal warm ischemia-reperfusion (I/R) injury drives acute kidney injury and transplant dys-function through endoplasmic reticulum (ER) stress. Although Activating Transcription Factor 6 (ATF6) modulates ER stress resolution via the unfolded protein response, its functional role in re-nal IRI remains undefined. Using murine model of warm renal I/R and hypoxia-reoxygenation (H/R)-treated HUVECs/HK-2 cells, we systematically investigated the expression of ATF6 and molecular mechanisms through RNA-seq, ChIP, and dual-luciferase assays. IRI significantly up-regulated the expression of ATF6 in renal tissues, especially in proximal tubule epithelial cells. Functionally, ATF6 activation reduced Cr, BUN, and inflammatory cytokines, whereas genet-ic/pharmacological suppression aggravated renal tubular damage. Mechanistic studies revealed ATF6 transcriptionally represses FHL2 by direct promoter binding. The interaction between FHL2 and TRAF6 promoted the TRAF6/NF-?B signaling pathway, and the phosphorylation levels of p65 and I?Ba were increased. ATF6 overexpression effectively counteracted FHL2-mediated NF-?B hyperactivation, establishing a protective axis where ATF6 mitigates inflammation via FHL2 sup-pression. This study identifies ATF6 as a renoprotective factor that suppresses FHL2 to inhibit TRAF6/NF-?B inflammation during IRI. The ATF6/FHL2/NF-?B axis provides mechanistic in-sights and therapeutic targets for ischemic renal injury and transplant complications. Overall design: We randomly assigned C57BL/6N mice to sham-operated (Sham, n=6) or I/R (n=6) groups. The I/R group received pentobarbital sodium anesthesia followed by renal pedicle occlusion. After 60 minutes of ischemia, we restored blood flow for 6h reperfusion before euthanasia and sample collection