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

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Particle and Fibre Toxicology

, 13:52

First Online: 27 September 2016Received: 11 March 2016Accepted: 20 September 2016DOI: 10.1186-s12989-016-0163-3

Cite this article as: Lin, YF., Chiu, IJ., Cheng, FY. et al. Part Fibre Toxicol 2015 13: 52. doi:10.1186-s12989-016-0163-3


BackgroundZinc 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.

ResultsWe 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.

ConclusionsZnO 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.

KeywordsHypoxia-inducible factor-1α Zinc oxide nanoparticles Nephrotoxicity Autophagy Apoptosis AbbreviationsAKIAcute kidney injury

AOAcridine orange

AVOsAcidic vesicular organelles

BUNBlood urea nitrogen

CTGFConnective tissue growth factor

EREndoplasmic reticulum

GOTGlutamate oxaloacetate transaminase

GPTGlutamate pyruvate transaminase



LC3Microtubule-associated protein light chain 3

PAI-1Plasminogen activator inhibitor-1

ROSReactive oxygen species

SSCSide scatter

ZnO NPsZinc oxide nanoparticles

Electronic supplementary materialThe online version of this article doi:10.1186-s12989-016-0163-3 contains supplementary material, which is available to authorized users.

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


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