title: Beneficial Effects ofMyo-Inositol Oxygenase Deficiency in Cisplatin-Induced AKI.
abstract: Overexpression of the proximal tubular enzymemyo-inositol oxygenase (MIOX) induces oxidant stressin vitroHowever, 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 orN-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.
authors.affiliation: Departments of Pathology and.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Dutta
authors.affiliation: Departments of Pathology and.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Kondeti
authors.affiliation: Departments of Pathology and.
authors.forename: Isha
authors.initials: I
authors.lastname: Sharma
authors.affiliation: Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.affiliation: Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Quaggin
authors.affiliation: Departments of Pathology and y-kanwar@northwestern.edu.|Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Kanwar
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000201:enzymology*; D000818:Animals; D002945:Cisplatin / Q000009:adverse effects*; D050562:Inositol Oxygenase / Q000172:deficiency* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic
chemical_list: D050562:Inositol Oxygenase; D002945:Cisplatin
keywords: cisplatin nephrotoxicity; myo-inositol oxygenase; oxidative stress; reactive oxygen species; renal injury