The role of hypoxia-inducible factor-1α in zinc oxide nanoparticle-induced nephrotoxicity in vitro and in vivo

Yuh-Feng Lin, I-Jen Chiu, Fong-Yu Cheng, Yu-Hsuan Lee, Ying-Jan Wang, Yung-Ho Hsu, Hui-Wen Chiu

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

BACKGROUND: Zinc oxide nanoparticles (ZnO NPs) are used in an increasing number of products, including rubber manufacture, cosmetics, pigments, food additives, medicine, chemical fibers and electronics. However, the molecular mechanisms underlying ZnO NP nephrotoxicity remain unclear. In this study, we evaluated the potential toxicity of ZnO NPs in kidney cells in vitro and in vivo.

RESULTS: We found that ZnO NPs were apparently engulfed by the HEK-293 human embryonic kidney cells and then induced reactive oxygen species (ROS) generation. Furthermore, exposure to ZnO NPs led to a reduction in cell viability and induction of apoptosis and autophagy. Interestingly, the ROS-induced hypoxia-inducible factor-1α (HIF-1α) signaling pathway was significantly increased following ZnO NPs exposure. Additionally, connective tissue growth factor (CTGF) and plasminogen activator inhibitor-1 (PAI-1), which are directly regulated by HIF-1 and are involved in the pathogenesis of kidney diseases, displayed significantly increased levels following ZnO NPs exposure in HEK-293 cells. HIF-1α knockdown resulted in significantly decreased levels of autophagy and increased cytotoxicity. Therefore, our results suggest that HIF-1α may have a protective role in adaptation to the toxicity of ZnO NPs in kidney cells. In an animal study, fluorescent ZnO NPs were clearly observed in the liver, lungs, kidneys, spleen and heart. ZnO NPs caused histopathological lesions in the kidney and increase in serum creatinine and blood urea nitrogen (BUN) which indicate possible renal possible damage. Moreover, ZnO NPs enhanced the HIF-1α signaling pathway, apoptosis and autophagy in mouse kidney tissues.

CONCLUSIONS: ZnO NPs may cause nephrotoxicity, and the results demonstrate the importance of considering the toxicological hazards of ZnO NP production and application, especially for medicinal use.

Original languageEnglish
Pages (from-to)52
JournalParticle and Fibre Toxicology
Volume13
Issue number1
DOIs
Publication statusPublished - Sep 27 2016

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Zinc Oxide
Hypoxia-Inducible Factor 1
Nanoparticles
Kidney
Autophagy
In Vitro Techniques
Toxicity
Reactive Oxygen Species
Food additives
Apoptosis
Rubber products
Connective Tissue Growth Factor
Food Additives
Cosmetics
HEK293 Cells
Blood Urea Nitrogen
Plasminogen Activator Inhibitor 1
Rubber
Kidney Diseases
Cytotoxicity

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The role of hypoxia-inducible factor-1α in zinc oxide nanoparticle-induced nephrotoxicity in vitro and in vivo. / Lin, Yuh-Feng; Chiu, I-Jen; Cheng, Fong-Yu; Lee, Yu-Hsuan; Wang, Ying-Jan; Hsu, Yung-Ho; Chiu, Hui-Wen.

In: Particle and Fibre Toxicology, Vol. 13, No. 1, 27.09.2016, p. 52.

Research output: Contribution to journalArticle

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