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Int. J. Mol. Sci. 2017, 18(3), 531;

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

Department of Pharmacology, Physiology, and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
West Virginia Wesleyan College, Buckhannon, WV 26201, USA
Author to whom correspondence should be addressed.
Academic Editor: Guido R. M. M. Haenen
Received: 17 January 2017 / Revised: 24 February 2017 / Accepted: 25 February 2017 / Published: 1 March 2017
(This article belongs to the Special Issue Nephrotoxicity)
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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. View Full-Text
Keywords: tenofovir; tenofovir disoproxil fumarate; nephrotoxicity; Fanconi Syndrome; HK-2 cells tenofovir; tenofovir disoproxil fumarate; nephrotoxicity; Fanconi Syndrome; HK-2 cells

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Murphy, R.A.; Stafford, R.M.; Petrasovits, B.A.; Boone, M.A.; Valentovic, M.A. Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity. Int. J. Mol. Sci. 2017, 18, 531.

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