Titanium Nanoparticle Inhalation Induces Renal Fibrosis in Mice via

Nov 18, 2014 - Anodically Grown Titania Nanotube Induced Cytotoxicity has Genotoxic Origins. M. Sheikh Mohamed , Aida Torabi , Maggie Paulose , D. Sak...
0 downloads 0 Views 3MB Size
Subscriber access provided by EASTERN KENTUCKY UNIVERSITY

Article

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

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Chemical Research in Toxicology is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 47

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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

ACS Paragon Plus Environment

Chemical Research in Toxicology

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 47

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

2

ACS Paragon Plus Environment

Taiwan.

E-mail:

Page 3 of 47

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Chemical Research in Toxicology

3

ACS Paragon Plus Environment

Chemical Research in Toxicology

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 47

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

ACS Paragon Plus Environment

Page 5 of 47

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Chemical Research in Toxicology

Key words: nanoparticles, oxidative stress, renal fibrosis, titanium dioxide

5

ACS Paragon Plus Environment

Chemical Research in Toxicology

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1. Introduction Titanium dioxide nanoparticles (Nano-TiO2,