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

Jung Yeon Yoo, Dae Ryong Cha, Borim Kim, Eun Jung An, Sae Rom Lee, Jin Joo Cha, Young Sun Kang, Jung Yeon Ghee, Jee Young Han, Yun Soo Bae

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 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-p22phox. Interaction of p22phox 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 p22phox-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.

Original languageEnglish
Article number108245
JournalCell Reports
Volume33
Issue number3
DOIs
StatePublished - 20 Oct 2020

Keywords

  • AKI
  • cytokine
  • HO, LPS
  • inflammation
  • Nox4
  • sepsis
  • SH3YL1
  • TLR4
  • tubular damage

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