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NADPH oxidase 4 mediates TGF-β1/Smad signaling pathway induced acute kidney injury in hypoxia

Sungkwon Cho1, Seong-Lan Yu2, Jaeku Kang3

  • 1Division of Nephrology and Department of Internal Medicine, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Republic of Korea.

Plos One
|July 19, 2019
PubMed

Insights

Hypoxia causes acute kidney injury (AKI). This study shows nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase 4 (Nox4) drives hypoxia-induced AKI by increasing reactive oxygen species (ROS). Targeting Nox4 may treat AKI.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cell Biology

Background:

  • Kidneys are highly susceptible to hypoxia, a common cause of acute kidney injury (AKI).
  • The role of nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase 4 (Nox4) in hypoxia-induced AKI requires further investigation.

Purpose of the Study:

  • To investigate the role of Nox4 in hypoxia-induced AKI using cellular and animal models.
  • To elucidate the signaling pathways involved in Nox4 activation during hypoxia.

Main Methods:

  • Hypoxic stimulation of human renal proximal tubular epithelial cells (HK-2) and assessment of Nox4 expression.
  • Investigated the involvement of TGF-β1 and Smad signaling pathway.
  • Utilized Nox4 siRNA and GKT137831 (Nox1/4 inhibitor) to block Nox4 activity.
  • Assessed reactive oxygen species (ROS) production and apoptosis.
  • Evaluated the protective effects of GKT137831 in an ischemia/reperfusion rat model.

Main Results:

  • Hypoxia significantly increased Nox4 expression in HK-2 cells.
  • TGF-β1 mediated Smad-dependent induction of Nox4.
  • Nox4 inhibition reduced ROS production and attenuated apoptosis, enhancing cell survival.
  • GKT137831 pretreatment protected against ischemia/reperfusion-induced AKI in rats, preserving kidney function and structure.

Conclusions:

  • Hypoxia induces renal cell apoptosis via TGF-β1/Smad pathway-mediated Nox4 activation and subsequent ROS generation.
  • Targeting Nox4 represents a potential therapeutic strategy for preventing and treating hypoxia-induced AKI.

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