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

View Article: PubMed Central - PubMed

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.

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

No MeSH data available.


Protein expression in the kidney tissues using IHC staining and western blot analysis. IHC was used to determine the expression levels of HIF-1α (a), LC3 (b) and cleaved-caspase-3 (c). d Western blot analysis of protein expression in kidney tissues. The mice were i.p. injected with ZnO NPs
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Fig7: Protein expression in the kidney tissues using IHC staining and western blot analysis. IHC was used to determine the expression levels of HIF-1α (a), LC3 (b) and cleaved-caspase-3 (c). d Western blot analysis of protein expression in kidney tissues. The mice were i.p. injected with ZnO NPs

Mentions: Next, HIF-1α, LC3 and cleaved-caspase-3 expression levels were examined in the kidney tissue using IHC staining (Fig. 7a-c). Significant increases in kidney expression of HIF-1α, LC3 and cleaved-caspase-3 were observed in the ZnO NP treatment group compared with the control group. In addition, proteins extracted from the kidney tissues were assayed by western blotting (Fig. 7d). We found that HIF-1α, CTGF, LC3-II and cleaved-caspase-3 protein levels were increased in the ZnO NP treatment group. Thus, ZnO NPs could cause renal histopathological lesions and regulate the HIF-1α signaling pathway in the kidney.Fig. 7


The role of hypoxia-inducible factor-1 α in zinc oxide nanoparticle-induced nephrotoxicity in vitro and in vivo
Protein expression in the kidney tissues using IHC staining and western blot analysis. IHC was used to determine the expression levels of HIF-1α (a), LC3 (b) and cleaved-caspase-3 (c). d Western blot analysis of protein expression in kidney tissues. The mice were i.p. injected with ZnO NPs
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5037597&req=5

Fig7: Protein expression in the kidney tissues using IHC staining and western blot analysis. IHC was used to determine the expression levels of HIF-1α (a), LC3 (b) and cleaved-caspase-3 (c). d Western blot analysis of protein expression in kidney tissues. The mice were i.p. injected with ZnO NPs
Mentions: Next, HIF-1α, LC3 and cleaved-caspase-3 expression levels were examined in the kidney tissue using IHC staining (Fig. 7a-c). Significant increases in kidney expression of HIF-1α, LC3 and cleaved-caspase-3 were observed in the ZnO NP treatment group compared with the control group. In addition, proteins extracted from the kidney tissues were assayed by western blotting (Fig. 7d). We found that HIF-1α, CTGF, LC3-II and cleaved-caspase-3 protein levels were increased in the ZnO NP treatment group. Thus, ZnO NPs could cause renal histopathological lesions and regulate the HIF-1α signaling pathway in the kidney.Fig. 7

View Article: PubMed Central - PubMed

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.

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

No MeSH data available.