Beneficial effects of myo-inositol oxygenase deficiency in cisplatin-induced AKI

Rajesh K. Dutta, Vinay K. Kondeti, Isha Sharma, Navdeep S. Chandel, Susan E. Quaggin, Yashpal S. Kanwar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Overexpression of the proximal tubular enzyme myo-inositol oxygenase (MIOX) induces oxidant stress in vitro. However, the relevance ofMIOX 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 andMIOX-knockout (MIOX-/-)mice with tubule-specificMIOX 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 andmore tubular injury and apoptosis, but these effectswere attenuated in cisplatin-treatedMIOX-/- mice. Similarly,MIOX-TGmice 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 dosedependently 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-kB binding to DNA, andNF-kB nuclear translocation in WT mice was exacerbated inMIOX-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 cisplatintreated MIOX-TG mice. Finally, analysis of genomic DNA inWT 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.

Original languageEnglish (US)
Pages (from-to)1421-1436
Number of pages16
JournalJournal of the American Society of Nephrology
Volume28
Issue number5
DOIs
StatePublished - May 2017

ASJC Scopus subject areas

  • Nephrology

Fingerprint Dive into the research topics of 'Beneficial effects of myo-inositol oxygenase deficiency in cisplatin-induced AKI'. Together they form a unique fingerprint.

Cite this