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Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity

Tenofovir (TFV) is an antiviral drug approved for treating Human Immunodeficiency Virus (HIV) and Hepatitis B. TFV is administered orally as the prodrug tenofovir disoproxil fumarate (TDF) which then is deesterified to the active drug TFV. TFV induces nephrotoxicity characterized by renal failure an...

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Autores principales: Murphy, Rachel A., Stafford, Reagan M., Petrasovits, Brooke A., Boone, Megann A., Valentovic, Monica A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372547/
https://www.ncbi.nlm.nih.gov/pubmed/28257038
http://dx.doi.org/10.3390/ijms18030531
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author Murphy, Rachel A.
Stafford, Reagan M.
Petrasovits, Brooke A.
Boone, Megann A.
Valentovic, Monica A.
author_facet Murphy, Rachel A.
Stafford, Reagan M.
Petrasovits, Brooke A.
Boone, Megann A.
Valentovic, Monica A.
author_sort Murphy, Rachel A.
collection PubMed
description Tenofovir (TFV) is an antiviral drug approved for treating Human Immunodeficiency Virus (HIV) and Hepatitis B. TFV is administered orally as the prodrug tenofovir disoproxil fumarate (TDF) which then is deesterified to the active drug TFV. TFV induces nephrotoxicity characterized by renal failure and Fanconi Syndrome. The mechanism of this toxicity remains unknown due to limited experimental models. This study investigated the cellular mechanism of cytotoxicity using a human renal proximal tubular epithelial cell line (HK-2). HK-2 cells were grown for 48 h followed by 24 to 72 h exposure to 0–28.8 μM TFV or vehicle, phosphate buffered saline (PBS). MTT (MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) and Trypan blue indicated that TFV diminished cell viability at 24–72 h. TFV decreased ATP levels at 72 h when compared to vehicle, reflecting mitochondrial dysfunction. TFV increased the oxidative stress biomarkers of protein carbonylation and 4-hydroxynonenol (4-HNE) adduct formation. Tumor necrosis factor alpha (TNFα) was released into the media following exposure to 14.5 and 28.8 μM TFV. Caspase 3 and 9 cleavage was induced by TFV compared to vehicle at 72 h. These studies show that HK-2 cells are a sensitive model for TFV cytotoxicity and suggest that mitochondrial stress and apoptosis occur in HK-2 cells treated with TFV.
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spelling pubmed-53725472017-04-10 Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity Murphy, Rachel A. Stafford, Reagan M. Petrasovits, Brooke A. Boone, Megann A. Valentovic, Monica A. Int J Mol Sci Article Tenofovir (TFV) is an antiviral drug approved for treating Human Immunodeficiency Virus (HIV) and Hepatitis B. TFV is administered orally as the prodrug tenofovir disoproxil fumarate (TDF) which then is deesterified to the active drug TFV. TFV induces nephrotoxicity characterized by renal failure and Fanconi Syndrome. The mechanism of this toxicity remains unknown due to limited experimental models. This study investigated the cellular mechanism of cytotoxicity using a human renal proximal tubular epithelial cell line (HK-2). HK-2 cells were grown for 48 h followed by 24 to 72 h exposure to 0–28.8 μM TFV or vehicle, phosphate buffered saline (PBS). MTT (MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) and Trypan blue indicated that TFV diminished cell viability at 24–72 h. TFV decreased ATP levels at 72 h when compared to vehicle, reflecting mitochondrial dysfunction. TFV increased the oxidative stress biomarkers of protein carbonylation and 4-hydroxynonenol (4-HNE) adduct formation. Tumor necrosis factor alpha (TNFα) was released into the media following exposure to 14.5 and 28.8 μM TFV. Caspase 3 and 9 cleavage was induced by TFV compared to vehicle at 72 h. These studies show that HK-2 cells are a sensitive model for TFV cytotoxicity and suggest that mitochondrial stress and apoptosis occur in HK-2 cells treated with TFV. MDPI 2017-03-01 /pmc/articles/PMC5372547/ /pubmed/28257038 http://dx.doi.org/10.3390/ijms18030531 Text en © 2017 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Murphy, Rachel A.
Stafford, Reagan M.
Petrasovits, Brooke A.
Boone, Megann A.
Valentovic, Monica A.
Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity
title Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity
title_full Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity
title_fullStr Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity
title_full_unstemmed Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity
title_short Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity
title_sort establishment of hk-2 cells as a relevant model to study tenofovir-induced cytotoxicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372547/
https://www.ncbi.nlm.nih.gov/pubmed/28257038
http://dx.doi.org/10.3390/ijms18030531
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