1. LPS-Induced Acute Kidney Injury Is Mediated by Nox4-SH3YL1.
- Author
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Yoo JY, Cha DR, Kim B, An EJ, Lee SR, Cha JJ, Kang YS, Ghee JY, Han JY, and Bae YS
- Subjects
- Animals, Cytokines metabolism, Disease Models, Animal, Female, Hydrogen Peroxide metabolism, Kidney pathology, Lipopolysaccharides pharmacology, Macrophages metabolism, Male, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, NADPH Oxidase 4 metabolism, NADPH Oxidases metabolism, Oxidation-Reduction, Reactive Oxygen Species metabolism, Signal Transduction drug effects, Acute Kidney Injury metabolism, Membrane Proteins genetics, NADPH Oxidase 4 genetics
- Abstract
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 H
2 O2 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-p22phox . Interaction of p22phox with SH3YL1 is triggered by LPS, and the complex induces H2 O2 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 p22phox -SH3YL1-Nox4, leading to H2 O2 generation, induces severe renal failure in the LPS-induced AKI model., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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