SUMOylation protects against sepsis-associated acute kidney injury by stabilizing IκBα.

Sepsis-associated acute kidney injury (SA-AKI) has an extremely high mortality rate, and its pathogenesis involves nuclear factor κB (NF-κB) overactivation with robust inflammation. SUMOylation is a form of post-translational modification implicated in the regulation of NF-κB signaling. The role and regulation of SUMOylation in SA-AKI are completely unknown. Here, we report that SUMOylation protects against SA-AKI by stabilizing IκBα to prevent NF-κB overactivation. UBC9, the sole SUMOylation E2 enzyme, was significantly upregulated in mouse models of SA-AKI induced by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP). In these models, knockout of Ubc9 specifically from kidney proximal tubules or pharmacologic inhibition of SUMOylation exacerbated inflammation and kidney injury. Consistently, genetic and pharmacologic inhibition of SUMOylation aggravated LPS-induced apoptosis and inflammatory response in cultured kidney tubular cells. Mechanistically, LPS promoted the SUMOylation of IκBα at two specific lysine sites, resulting in IκBα stabilization and thereby counteracting NF-κB overactivation. Collectively, these data unveil SUMOylation as an intrinsic protective mechanism that is activated upon septic stress to quench the pro-inflammatory signaling of NF-κB in kidneys, suggesting a new therapeutic strategy for SA-AKI.