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Titanium nanoparticles inhalation induces renal fibrosis in mice via an oxidative stress-up-regulated transforming growth factor-# pathway Kuo-Tong Huang, Cheng-Tien Wu, Kuo-How Huang, Wei-Chou Lin, ChangMu Chen, Siao-Syun Guan, Chih-Kang Chiang, and Shing-Hwa Liu Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/tx500287f • Publication Date (Web): 18 Nov 2014 Downloaded from http://pubs.acs.org on November 24, 2014
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Chemical Research in Toxicology
Titanium nanoparticles inhalation induces renal fibrosis in mice via an oxidative stress-up-regulated transforming growth factor-β pathway
Kuo-Tong Huang,†,‡,# Cheng-Tien Wu,†,# Kuo-How Huang, ¶ ,# Wei-Chou Lin,§ Chang-Mu Chen,ǁ Siao-Syun Guan,†,¤ Chih-Kang Chiang,†, ,* Shing-Hwa Liu†,$,* ┴
†
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei,
Taiwan; ‡
Department of Nephrology, Department of Internal Medicine, National Taiwan
University Hospital, Taipei, Taiwan; ¶
Department of Urology, College of Medicine, National Taiwan University, Taipei,
Taiwan; §
Department of pathology, National Taiwan University Hospital, Taipei, Taiwan;
ǁ
Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan;
¤
Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan;
┴
Departments of Integrated Diagnostics & Therapeutics and Internal Medicine,
National Taiwan University Hospital, Taipei, Taiwan; $
Department of Medical Research, China Medical University Hospital, China Medical
University, Taichung, Taiwan;
#
These authors contributed equally to this work.
*Address Correspondence to: Shing-Hwa Liu, PhD, Institute of Toxicology, College 1
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Medicine, National Taiwan University, Taipei, Taiwan. TEL: +886-2-23123456 ext. 88605. FAX: +886-2-23410217. E-mail:
[email protected]; or Chih-Kang Chiang, MD, PhD, Departments of Integrated Diagnostics & Therapeutics and Medicine,
National
Taiwan
University
Hospital,
Taipei,
[email protected].
Running title: Nano-titanium dioxide Accelerates Renal Injury
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Taiwan.
E-mail:
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Abstract Titanium dioxide nanoparticles (Nano-TiO2) are gradually extensively used in the clinical, industry and daily life. Accumulation studies showed that Nano-TiO2 exposure is able to cause injuries in various animal organs, including lung, liver, spleen, and kidney. However, it remains unclear whether exposure of Nano-TiO2 by inhalation causes renal fibrosis. Here, we investigated the role of reactive oxygen species (ROS)/reactive nitrogen species (RNS)-related signalling molecules in the chronic renal damage after Nano-TiO2 inhalation in mice. Mice were treated with Nano-TiO2 (0.1, 0.25, and 0.5 mg/week) or microparticle-TiO2 (0.5 mg/week) by non-surgical intratracheal instillation for 4 weeks. The results showed that Nano-TiO2 inhalation increased renal pathological changes in a dose-dependent manner. No renal pathological changes were observed in microparticle-TiO2-instilled mice. Nano-TiO2 (0.5 mg/week) possessed the ability to precipitate in the kidneys determined by transmission electron microscopy and increased serum levels of blood urea nitrogen. The expressions of markers of ROS/RNS and renal fibrosis markers, including nitrotyrosine, inducible nitric oxide synthase, hypoxia inducible factor-1α (HIF-1α), heme oxygenase 1, transforming growth factor-β (TGFβ), and collagen I determined by immunohistochemical staining were increased in the kidneys. Furthermore, Nano-TiO2-induced
renal
injury
could
be
mitigated
by
iNOS
inhibitor
aminoguanidine and ROS scavenger N-acetylcysteine treatment in transcription level. The in vitro experiments showed that Nano-TiO2 significantly and dose-dependently increased the ROS production and the expressions of HIF-1α and TGFβ in human renal proximal tubular cells, which could be reversed by N-acetylcysteine treatment. Taken together, these results suggest Nano-TiO2 inhalation might induce the renal fibrosis through a ROS/RNS-related HIF-1α-up-regulated TGF-β signalling pathway. 4
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Chemical Research in Toxicology
Key words: nanoparticles, oxidative stress, renal fibrosis, titanium dioxide
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1. Introduction Titanium dioxide nanoparticles (Nano-TiO2,
