Cargando…
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...
Autores principales: | , , , , |
---|---|
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 |
_version_ | 1782518640669622272 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5372547 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT murphyrachela establishmentofhk2cellsasarelevantmodeltostudytenofovirinducedcytotoxicity AT staffordreaganm establishmentofhk2cellsasarelevantmodeltostudytenofovirinducedcytotoxicity AT petrasovitsbrookea establishmentofhk2cellsasarelevantmodeltostudytenofovirinducedcytotoxicity AT boonemeganna establishmentofhk2cellsasarelevantmodeltostudytenofovirinducedcytotoxicity AT valentovicmonicaa establishmentofhk2cellsasarelevantmodeltostudytenofovirinducedcytotoxicity |