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

Jung-Yeon Yoo1, Dae Ryong Cha2, Borim Kim1

  • 1Department of Life Sciences, Ewha Womans University, Seoul 120-750, Korea.

Cell Reports
|October 21, 2020
PubMed

Insights

SH3YL1 regulates NADPH oxidase 4 (Nox4) to mediate lipopolysaccharide-induced hydrogen peroxide generation, a key factor in acute kidney injury (AKI). SH3YL1 knockout mice exhibited reduced AKI severity, indicating its critical role in this condition.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Nephrology

Background:

  • Cytosolic proteins regulate NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (Nox) isozymes.
  • Lipopolysaccharide (LPS) triggers inflammatory responses and oxidative stress, contributing to acute kidney injury (AKI).

Purpose of the Study:

  • To investigate the role of SH3YL1 (Src homology 3 domain-containing YSC84-like 1) as a cytosolic regulator of Nox4 in LPS-induced AKI.
  • To elucidate the molecular mechanism by which SH3YL1 contributes to renal failure.

Main Methods:

  • Investigated the interaction between SH3YL1, Nox4, and p22phox using cellular assays.
  • Utilized SH3YL1 knockout mice to assess the in vivo impact on LPS-induced AKI.
  • Measured biomarkers of kidney injury, cytokine expression, macrophage infiltration, and tubular damage.

Main Results:

  • SH3YL1 forms a complex with Nox4-p22phox, triggered by LPS, leading to hydrogen peroxide (H2O2) generation and pro-inflammatory cytokine expression.
  • SH3YL1 knockout mice showed significantly reduced AKI biomarkers, lower pro-inflammatory cytokine secretion, decreased macrophage infiltration, and less tubular damage compared to wild-type mice.
  • The formation of a p22phox-SH3YL1-Nox4 ternary complex is crucial for H2O2 generation and severe renal failure in LPS-induced AKI.

Conclusions:

  • SH3YL1 acts as a critical cytosolic regulator of Nox4 in the context of LPS-induced AKI.
  • Targeting the SH3YL1-Nox4 interaction may offer a therapeutic strategy for mitigating renal failure in AKI.
Keywords:
AKIH(2)O(2,) LPSNox4SH3YL1TLR4cytokineinflammationsepsistubular damage

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