Comprehensive assessment of nephrotoxicity of intravenously administered sodium-oleate-coated ultra-small superparamagnetic iron oxide (USPIO) and titanium dioxide (TiO₂) nanoparticles in rats

Abstract

As a main excretory organ, kidney is predisposed to direct/indirect injury. We addressed the potential nephrotoxic effects following expositions of healthy rats to nanoparticle (NP) loads relevant to humans in a situation of 100% bioavailability. Up to 4 weeks after administration, a single iv bolus of oleate-coated ultra-small superparamagnetic iron oxide NPs (in dose of 0.1%, 1.0% and 10.0% of LD50) or TiO₂ NPs (1.0% of LD50) did not elicit decline in renal function, damage to proximal tubules, alterations in: renal histology or expression of pro-inflammatory/pro-fibrotic genes, markers of systemic or local renal micro-inflammation or oxidative damage. Antioxidant enzyme activities in renal cortex, mildly elevated at 24 h, completely restored at later time points. Data obtained by multifaceted approach enable the prediction of human nephrotoxicity during preclinical studies, and may serve as comparison for alternative testing strategies using in vitro and in silico methods essential for the NP-nephrotoxicity risk assessment.

Keywords::

• nanoparticles
• renal function
• oxidative stress
• micro-inflammation
• gene expression
• renal histology

Acknowledgement

This study was supported by 7FP EC grant to NanoTest project, contract No. HEALTH-2007-201335, and in part by grants from Ministry of Education of Slovak Republic, No. VEGA 2/0149/12, and the Deutsche Forschungsgemeinschaft (to PB: BO 3755/1-1 and SFB TRR57, projects nP25 and Q1). Authors wish to thank MVDr. Katarína Ambrušová, the Head of the Animal Facility at Slovak Medical University in Bratislava, for excellent assistance throughout the experiment; Dipl. Tex. Des. Zuzana Šebeková from the Academy of Fine Arts and Design, Bratislava, for excellent technical assistance at sacrifice, and RNDr. Vladimír Mlynárik from Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland, for his valuable advices and comments regarding MRI data processing.