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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.


Related in: MedlinePlus

ZnO NPs pathways and effects in kidney cells. ZnO NPs induce apoptosis and the HIF-1α signaling pathway through ROS generation, eventually leading to nephrotoxicity. Furthermore, ZnO NP-induced autophagy may be mediated by the induction of the HIF-1α signaling pathway. Inhibition of HIF-1α by HIF-1α siRNA increases the cytotoxicity, indicating a protective role of HIF-1α. In addition, CTGF and PAI-1, which are directly regulated by HIF and are related to the renal fibrosis, are increased after ZnO NP treatment
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Fig8: ZnO NPs pathways and effects in kidney cells. ZnO NPs induce apoptosis and the HIF-1α signaling pathway through ROS generation, eventually leading to nephrotoxicity. Furthermore, ZnO NP-induced autophagy may be mediated by the induction of the HIF-1α signaling pathway. Inhibition of HIF-1α by HIF-1α siRNA increases the cytotoxicity, indicating a protective role of HIF-1α. In addition, CTGF and PAI-1, which are directly regulated by HIF and are related to the renal fibrosis, are increased after ZnO NP treatment

Mentions: In the present study, the results showed that ZnO NPs can induce apoptosis and autophagy, accompanied by ROS and the activation of the HIF-1α signaling pathway, eventually leading to nephrotoxicity (Fig. 8). Our findings suggest that ZnO NP-induced autophagy is associated with HIF-1α signaling, which may be an important mechanism and protective outcome of kidney diseases caused by ZnO NPs. In the animal study, the histological analysis of kidneys from ZnO NP-treated mice showed histopathological lesions. Furthermore, serum biochemical analysis showed that BUN, creatinine, GPT and GOT activities, which indicate possible renal and liver damage, were significantly elevated in ZnO NP-treated mice. Therefore, it is necessary for all researchers or patients who are regularly exposed to ZnO NPs to consider the toxicological hazards and institute appropriate safety measures.Fig. 8


The role of hypoxia-inducible factor-1 α in zinc oxide nanoparticle-induced nephrotoxicity in vitro and in vivo
ZnO NPs pathways and effects in kidney cells. ZnO NPs induce apoptosis and the HIF-1α signaling pathway through ROS generation, eventually leading to nephrotoxicity. Furthermore, ZnO NP-induced autophagy may be mediated by the induction of the HIF-1α signaling pathway. Inhibition of HIF-1α by HIF-1α siRNA increases the cytotoxicity, indicating a protective role of HIF-1α. In addition, CTGF and PAI-1, which are directly regulated by HIF and are related to the renal fibrosis, are increased after ZnO NP treatment
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5037597&req=5

Fig8: ZnO NPs pathways and effects in kidney cells. ZnO NPs induce apoptosis and the HIF-1α signaling pathway through ROS generation, eventually leading to nephrotoxicity. Furthermore, ZnO NP-induced autophagy may be mediated by the induction of the HIF-1α signaling pathway. Inhibition of HIF-1α by HIF-1α siRNA increases the cytotoxicity, indicating a protective role of HIF-1α. In addition, CTGF and PAI-1, which are directly regulated by HIF and are related to the renal fibrosis, are increased after ZnO NP treatment
Mentions: In the present study, the results showed that ZnO NPs can induce apoptosis and autophagy, accompanied by ROS and the activation of the HIF-1α signaling pathway, eventually leading to nephrotoxicity (Fig. 8). Our findings suggest that ZnO NP-induced autophagy is associated with HIF-1α signaling, which may be an important mechanism and protective outcome of kidney diseases caused by ZnO NPs. In the animal study, the histological analysis of kidneys from ZnO NP-treated mice showed histopathological lesions. Furthermore, serum biochemical analysis showed that BUN, creatinine, GPT and GOT activities, which indicate possible renal and liver damage, were significantly elevated in ZnO NP-treated mice. Therefore, it is necessary for all researchers or patients who are regularly exposed to ZnO NPs to consider the toxicological hazards and institute appropriate safety measures.Fig. 8

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.


Related in: MedlinePlus