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

TL;DR

The study finds that ATF6 protects the kidneys from injury by reducing inflammation and regulating a key signaling pathway involving FHL2 and NF-κB.

Contribution

The novel contribution is identifying ATF6 as a renoprotective factor through its regulation of the FHL2/NF-κB pathway in renal ischemia-reperfusion injury.

Findings

ATF6 activation improves renal function and reduces inflammation in renal I/R injury.

ATF6 represses FHL2 expression via direct promoter binding.

ATF6 counteracts FHL2-mediated NF-κB activation, forming a protective signaling axis.

Abstract

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.

•Renal I/R injury upregulates ATF6 in proximal tubular epithelial cells•ATF6 activation ameliorates renal function and attenuates inflammation•ATF6 transcriptionally represses FHL2 expression via direct promoter binding•ATF6 mitigates NF-κB activation by disrupting the FHL2-TRAF6 interaction

Renal I/R injury upregulates ATF6 in proximal tubular epithelial cells

ATF6 activation ameliorates renal function and attenuates inflammation

ATF6 transcriptionally represses FHL2 expression via direct promoter binding

ATF6 mitigates NF-κB activation by disrupting the FHL2-TRAF6 interaction

Physiology; Molecular biology

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