Beneficial Effects of Myo-Inositol Oxygenase Deficiency in Cisplatin-Induced AKI

J Am Soc Nephrol. 2017 May;28(5):1421-1436. doi: 10.1681/ASN.2016070744. Epub 2016 Nov 28.

Abstract

Overexpression of the proximal tubular enzyme myo-inositol oxygenase (MIOX) induces oxidant stress in vitro However, the relevance of MIOX to tubular pathobiology remains enigmatic. To investigate the role of MIOX in cisplatin-induced tubular AKI, we generated conditional MIOX-overexpressing transgenic (MIOX-TG) mice and MIOX-knockout (MIOX-/-) mice with tubule-specific MIOX overexpression or knockout, respectively. Compared with cisplatin-treated wild-type (WT) mice, cisplatin-treated MIOX-TG mice had even greater increases in urea, creatinine, and KIM-1 levels and more tubular injury and apoptosis, but these effects were attenuated in cisplatin-treated MIOX-/- mice. Similarly, MIOX-TG mice had the highest and MIOX-/- mice had the lowest renal levels of Bax, cleaved caspase-3, and NADPH oxidase-4 expression and reactive oxygen species (ROS) generation after cisplatin treatment. In vitro, cisplatin dose-dependently increased ROS generation in LLC-PK1 cells. Furthermore, MIOX overexpression in these cells accentuated cisplatin-induced ROS generation and perturbations in the ratio of GSH to oxidized GSH, whereas MIOX-siRNA or N-acetyl cysteine treatment attenuated these effects. Additionally, the cisplatin-induced enhancement of p53 activation, NF-κB binding to DNA, and NF-κB nuclear translocation in WT mice was exacerbated in MIOX-TG mice but absent in MIOX-/- mice. In vitro, MIOX-siRNA or NAC treatment reduced the dose-dependent increase in p53 expression induced by cisplatin. We also observed a remarkable influx of inflammatory cells and upregulation of cytokines in kidneys of cisplatin-treated MIOX-TG mice. Finally, analysis of genomic DNA in WT mice revealed cisplatin-induced hypomethylation of the MIOX promoter. These data suggest that MIOX overexpression exacerbates, whereas MIOX gene disruption protects against, cisplatin-induced AKI.

Keywords: cisplatin nephrotoxicity; myo-inositol oxygenase; oxidative stress; reactive oxygen species; renal injury.

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / enzymology*
  • Animals
  • Cisplatin / adverse effects*
  • Inositol Oxygenase / deficiency*
  • Inositol Oxygenase / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic

Substances

  • Inositol Oxygenase
  • Cisplatin