ATF6 ameliorates renal warm ischemia-reperfusion injury through FHL2-mediated NF-κB signaling pathway.

Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury and transplant dysfunction, involving endoplasmic reticulum stress. Although activating transcription factor 6 (ATF6) regulates ER stress resolution through the unfolded protein response, its specific role in renal I/R injury remains undefined. Here, we employed murine models of renal I/R and cellular hypoxia/reoxygenation (H/R) models to systematically investigate ATF6's function. Our results show that I/R injury significantly upregulates ATF6 expression, particularly in proximal tubular epithelial cells. Functionally, ATF6 activation improved renal function and attenuated inflammation, whereas its inhibition exacerbated tubular damage. Mechanistically, we demonstrated that ATF6 transcriptionally represses four and a half LIM domain protein 2 (FHL2) through direct promoter binding. FHL2, in turn, interacts with TRAF6 to activate the nuclear factor kappa-B (NF-κB) pathway. ATF6 overexpression effectively counteracted FHL2-mediated NF-κB hyperactivation, establishing a protective ATF6/FHL2/NF-κB axis. These findings identify ATF6 as a key renoprotective factor and reveal mechanistic avenues for potential therapies targeting renal I/R injury and transplant complications.