LPS-Induced Acute Kidney Injury Is Mediated by Nox4-SH3YL1

Cytosolic proteins are required for regulation of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (Nox) isozymes. Here we show that Src homology 3 (SH3) domain-containing YSC84-like 1 (SH3YL1), as a Nox4 cytosolic regulator, mediates lipopolysaccharide (LPS)-induced H₂O₂ generation, leading to acute kidney injury. The SH3YL1, Ysc84p/Lsb4p, Lsb3p, and plant FYVE proteins (SYLF) region and SH3 domain of SH3YL1 contribute to formation of a complex with Nox4-p22^phox. Interaction of p22^phox with SH3YL1 is triggered by LPS, and the complex induces H₂O₂ generation and pro-inflammatory cytokine expression in mouse tubular epithelial cells. After LPS injection, SH3YL1 knockout mice show lower levels of acute kidney injury biomarkers, decreased secretion of pro-inflammatory cytokines, decreased infiltration of macrophages, and reduced tubular damage compared with wild-type (WT) mice. The results strongly suggest that SH3YL1 is involved in renal failure in LPS-induced acute kidney injury (AKI) mice. We demonstrate that formation of a ternary complex of p22^phox-SH3YL1-Nox4, leading to H₂O₂ generation, induces severe renal failure in the LPS-induced AKI model. Yoo et al. demonstrate that SH3YL1 serves as a cytosolic regulator of Nox4 to mediate LPS-dependent H₂O₂ generation. The Nox4-SH3YL1 axis stimulates expression of pro-inflammatory cytokines and then triggers apoptosis of tubular cells, leading to AKI. SH3YL1 plays an important role in diseases associated with H₂O₂ produced by Nox4.