Cargando…

Understanding the Role of the Lateral Dimensional Property of Graphene Oxide on Its Interactions with Renal Cells

Renal excretion is expected to be the major route for the elimination of biomedically applied nanoparticles from the body. Hence, understanding the nanomedicine–kidney interaction is crucially required, but it is still far from being understood. Herein, we explored the lateral dimension- (~70 nm and...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Wei, Wang, Bing, Liang, Shanshan, Wang, Meng, Zheng, Lingna, Xu, Si, Wang, Jiali, Fang, Hao, Yang, Pu, Feng, Weiyue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9697150/
https://www.ncbi.nlm.nih.gov/pubmed/36432058
http://dx.doi.org/10.3390/molecules27227956
_version_ 1784838488873500672
author Chen, Wei
Wang, Bing
Liang, Shanshan
Wang, Meng
Zheng, Lingna
Xu, Si
Wang, Jiali
Fang, Hao
Yang, Pu
Feng, Weiyue
author_facet Chen, Wei
Wang, Bing
Liang, Shanshan
Wang, Meng
Zheng, Lingna
Xu, Si
Wang, Jiali
Fang, Hao
Yang, Pu
Feng, Weiyue
author_sort Chen, Wei
collection PubMed
description Renal excretion is expected to be the major route for the elimination of biomedically applied nanoparticles from the body. Hence, understanding the nanomedicine–kidney interaction is crucially required, but it is still far from being understood. Herein, we explored the lateral dimension- (~70 nm and ~300 nm), dose- (1, 5, and 15 mg/kg in vivo and 0.1~250 μg/mL in vitro), and time-dependent (48 h and 7 d in vivo) deposition and injury of PEGylated graphene oxide sheets (GOs) in the kidney after i.v. injection in mice. We specially investigated the cytotoxic effects on three typical kidney cell types with which GO renal excretion is related: human renal glomerular endothelial cells (HRGECs) and human podocytes, and human proximal tubular epithelial cells (HK-2). By using in vivo fluorescence imaging and in situ Raman imaging and spectroscopic analysis, we revealed that GOs could gradually be eliminated from the kidneys, where the glomeruli and renal tubules are their target deposition sites, but only the high dose of GO injection induced obvious renal histological and ultrastructural changes. We showed that the high-dose GO-induced cytotoxicity included a cell viability decrease and cellular apoptosis increase. GO uptake by renal cells triggered cellular membrane damage (intracellular LDH release) and increased levels of oxidative stress (ROS level elevation and a decrease in the balance of the GSH/GSSG ratio) accompanied by a mitochondrial membrane potential decrease and up-regulation of the expression of pro-inflammatory cytokines TNF-α and IL-18, resulting in cellular apoptosis. GO treatments activated Keap1/Nrf2 signaling; however, the antioxidant function of Nrf2 could be inhibited by apoptotic engagement. GO-induced cytotoxicity was demonstrated to be associated with oxidative stress and an inflammation reaction. Generally, the l-GOs presented more pronounced cytotoxicity and more severe cellular injury than s-GOs did, demonstrating lateral size-dependent toxicity to the renal cells. More importantly, GO-induced cytotoxicity was independent of renal cell type. The results suggest that the dosage of GOs in biomedical applications should be considered and that more attention should be paid to the ability of a high dose of GO to cause renal deposition and potential nephrotoxicity.
format Online
Article
Text
id pubmed-9697150
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-96971502022-11-26 Understanding the Role of the Lateral Dimensional Property of Graphene Oxide on Its Interactions with Renal Cells Chen, Wei Wang, Bing Liang, Shanshan Wang, Meng Zheng, Lingna Xu, Si Wang, Jiali Fang, Hao Yang, Pu Feng, Weiyue Molecules Article Renal excretion is expected to be the major route for the elimination of biomedically applied nanoparticles from the body. Hence, understanding the nanomedicine–kidney interaction is crucially required, but it is still far from being understood. Herein, we explored the lateral dimension- (~70 nm and ~300 nm), dose- (1, 5, and 15 mg/kg in vivo and 0.1~250 μg/mL in vitro), and time-dependent (48 h and 7 d in vivo) deposition and injury of PEGylated graphene oxide sheets (GOs) in the kidney after i.v. injection in mice. We specially investigated the cytotoxic effects on three typical kidney cell types with which GO renal excretion is related: human renal glomerular endothelial cells (HRGECs) and human podocytes, and human proximal tubular epithelial cells (HK-2). By using in vivo fluorescence imaging and in situ Raman imaging and spectroscopic analysis, we revealed that GOs could gradually be eliminated from the kidneys, where the glomeruli and renal tubules are their target deposition sites, but only the high dose of GO injection induced obvious renal histological and ultrastructural changes. We showed that the high-dose GO-induced cytotoxicity included a cell viability decrease and cellular apoptosis increase. GO uptake by renal cells triggered cellular membrane damage (intracellular LDH release) and increased levels of oxidative stress (ROS level elevation and a decrease in the balance of the GSH/GSSG ratio) accompanied by a mitochondrial membrane potential decrease and up-regulation of the expression of pro-inflammatory cytokines TNF-α and IL-18, resulting in cellular apoptosis. GO treatments activated Keap1/Nrf2 signaling; however, the antioxidant function of Nrf2 could be inhibited by apoptotic engagement. GO-induced cytotoxicity was demonstrated to be associated with oxidative stress and an inflammation reaction. Generally, the l-GOs presented more pronounced cytotoxicity and more severe cellular injury than s-GOs did, demonstrating lateral size-dependent toxicity to the renal cells. More importantly, GO-induced cytotoxicity was independent of renal cell type. The results suggest that the dosage of GOs in biomedical applications should be considered and that more attention should be paid to the ability of a high dose of GO to cause renal deposition and potential nephrotoxicity. MDPI 2022-11-17 /pmc/articles/PMC9697150/ /pubmed/36432058 http://dx.doi.org/10.3390/molecules27227956 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Wei
Wang, Bing
Liang, Shanshan
Wang, Meng
Zheng, Lingna
Xu, Si
Wang, Jiali
Fang, Hao
Yang, Pu
Feng, Weiyue
Understanding the Role of the Lateral Dimensional Property of Graphene Oxide on Its Interactions with Renal Cells
title Understanding the Role of the Lateral Dimensional Property of Graphene Oxide on Its Interactions with Renal Cells
title_full Understanding the Role of the Lateral Dimensional Property of Graphene Oxide on Its Interactions with Renal Cells
title_fullStr Understanding the Role of the Lateral Dimensional Property of Graphene Oxide on Its Interactions with Renal Cells
title_full_unstemmed Understanding the Role of the Lateral Dimensional Property of Graphene Oxide on Its Interactions with Renal Cells
title_short Understanding the Role of the Lateral Dimensional Property of Graphene Oxide on Its Interactions with Renal Cells
title_sort understanding the role of the lateral dimensional property of graphene oxide on its interactions with renal cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9697150/
https://www.ncbi.nlm.nih.gov/pubmed/36432058
http://dx.doi.org/10.3390/molecules27227956
work_keys_str_mv AT chenwei understandingtheroleofthelateraldimensionalpropertyofgrapheneoxideonitsinteractionswithrenalcells
AT wangbing understandingtheroleofthelateraldimensionalpropertyofgrapheneoxideonitsinteractionswithrenalcells
AT liangshanshan understandingtheroleofthelateraldimensionalpropertyofgrapheneoxideonitsinteractionswithrenalcells
AT wangmeng understandingtheroleofthelateraldimensionalpropertyofgrapheneoxideonitsinteractionswithrenalcells
AT zhenglingna understandingtheroleofthelateraldimensionalpropertyofgrapheneoxideonitsinteractionswithrenalcells
AT xusi understandingtheroleofthelateraldimensionalpropertyofgrapheneoxideonitsinteractionswithrenalcells
AT wangjiali understandingtheroleofthelateraldimensionalpropertyofgrapheneoxideonitsinteractionswithrenalcells
AT fanghao understandingtheroleofthelateraldimensionalpropertyofgrapheneoxideonitsinteractionswithrenalcells
AT yangpu understandingtheroleofthelateraldimensionalpropertyofgrapheneoxideonitsinteractionswithrenalcells
AT fengweiyue understandingtheroleofthelateraldimensionalpropertyofgrapheneoxideonitsinteractionswithrenalcells