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

doi:10.3390/ijms18030531

Cited by 15 publications

(16 citation statements)

References 38 publications

(52 reference statements)

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“…Our findings are supported by a recent report by Murphy et al 30 These authors have investigated the cellular mechanism of TDF cytotoxicity using a human renal proximal tubular epithelial cell line (HK-2).They have demonstrated that incubation of HK-2 cells with different concentrations of TDF resulted in decreased cell viability, increased oxidative stress biomarkers–protein carbonylation and 4-hydroxynonenol, mitochondrial dysfunction and increased expression of cleaved caspases 3 and 9. These authors have suggested that TDF induces apoptosis in HK-2 cells and that mitochondrial dysfunction may be a major contributing factor to loss of cell viability.…”

Section: Discussionsupporting

confidence: 90%

Mitochondrial pathway of apoptosis and necrosis contribute to tenofovir disoproxil fumarate–induced renal damage in rats

et al. 2018

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Tenofovir disoproxil fumarate (TDF) is currently the only nucleotide analogue reverse-transcriptase inhibitor that is approved by the Food and Drug administration (FDA), USA, for the treatment of human immunodeficiency virus (HIV) infection. In recent days, renal toxicity is becoming common i HIV patients treated with TDF. However, the mechanism of tenofovir nephrotoxicity is not clear. We hypothesized that mitochondrial pathway of apoptosis, poly [ADP-ribose] polymerase (PARP) overactivation and neutrophil infiltration may contribute to tenofovir-induced renal damage. Renal damage was induced in adult male Wistar rats by the oral administration of 600 mg/kg body weight daily for five consecutive weeks. Kidneys were removed and used for histological and biochemical analyses. Apoptosis was detected by terminal deoxynucleotidyl transferase biotin–deoxyuridine triphosphate nick end-labelling (TUNEL) assay and caspase 3 activity and protein expression; mitochondrial pathway of apoptosis by cyt c release; and PARP activation by immunofluorescence, immunohistochemistry and Western blot techniques. Myeloperoxidase (MPO) activity was measured as a marker of neutrophil infiltration. TDF administration resulted in increased number of TUNEL-positive cells, activation of caspase 3 and release of cyt c from mitochondria into the cytosol in the kidneys. There was increased nuclear localization of PARP as well as increase in its protein level in the TDF-treated rat kidneys. In addition, renal MPO activity was increased ninefold as compared to controls. The results of the present study show that mitochondrial apoptotic pathway, PARP overactivation and neutrophil infiltration contribute to tenofovir-induced renal damage in rats.

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Section: Discussionsupporting

confidence: 90%

Mitochondrial pathway of apoptosis and necrosis contribute to tenofovir disoproxil fumarate–induced renal damage in rats

et al. 2018

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“…We found that gentamicin has a higher toxicity to HK‐2 than HEK‐293, which was expected since the proximal tubule cells are more sensitive to aminoglycosides, such as gentamicin. This effect was also observed in other studies, even for animal strains such as proximal and distal convoluted tubulus LLC‐PK1 and MDCK, respectively …”

Section: Resultssupporting

confidence: 86%

In vitro evaluation of biomarkers of nephrotoxicity through gene expression using gentamicin

Campos

Almeida

Grossi

et al. 2018

J Biochem & Molecular Tox

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Acute renal failure is one of the most frequent effects observed after taking medicine. Such situations have been tardily discovered, given that existing methods for assessing toxicity are not predictive. In this light, the present work evaluated the effects of gentamicin, a form of nephrotoxic drug, on HK-2 and HEK-293 cells. By using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and flow cytometry, both cells demonstrated that cytotoxicity occurs in a dose-dependent manner through the processes of apoptosis and cell necrosis. Gene expression analysis showed a relative increase of expression for genes related to cell processes and classic biomarkers, such as TP53, CASP3, CASP8, CASP9, ICAM-1, EXOC3, KIM-1, and CST3. A decrease in expression for genes BCL2L1 and EGF was observed. This study, therefore, indicates that, when the methods are used together, gene expression analysis is able to evaluate the nephrotoxic potential of a substance.

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“…Therefore, proximal convoluted tubules are the main toxic target cells of inorganic mercury. The HK-2 cells, which are immortalized human renal cortex proximal convoluted tubule epithelial cells, have various characteristics of normal cortical juxta convoluted tubule epithelial cells, and are often used as an effective model for the study of mercury nephrotoxicity in vitro [ 33 , 34 ]. Therefore, the Hk-2 cells were employed in the present study as well.…”

Section: Discussionmentioning

confidence: 99%

Cinnabar protects serum-nutrient starvation induced apoptosis by improving intracellular oxidative stress and inhibiting the expression of CHOP and PERK

Ding

Wang³

et al. 2021

Biochemistry and Biophysics Reports

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Cinnabar has been used for treatment of various disorders for thousands of years. The medical use of cinnabar, however, has been controversial because of its heavy metal mercury content. A large quantity of studies indicate that the toxicity of cinnabar is far below other inorganic or organic mercury-containing compounds. Yet, the underlying molecular basis has remained unresolved. Here, we investigated the beneficial effects of cinnabar on serum-nutrient starvation-elicited cell injury. Our findings showed that treatment of human renal proximal tubular cells (HK-2) with 4 nM cinnabar effectively inhibited nutrient deprivation induced apoptosis, reduced intracellular reactive oxygen species generation and increased GSH content, which was contrary to the exacerbated apoptotic cell death and oxidative stress in cells treated with HgCl 2 at equal mercury concentration. In addition, cinnabar exerted robust antioxidative and antiapoptotic effects in cells under dual challenges of nutrient deprivation and treatment of H 2 O 2 . The protein expression levels of both CHOP and PERK were remarkably down-regulated in the cells treated with cinnabar compared to the control cells or cells treated with HgCl 2 . Overall, our data indicates that cinnabar at low concentration exerts anti-oxidative stress and anti-apoptosis effects by inhibiting the expression of the endoplasmic reticulum stress pathway proteins CHOP and PERK.

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

Cited by 15 publications

References 38 publications

Mitochondrial pathway of apoptosis and necrosis contribute to tenofovir disoproxil fumarate–induced renal damage in rats

Mitochondrial pathway of apoptosis and necrosis contribute to tenofovir disoproxil fumarate–induced renal damage in rats

In vitro evaluation of biomarkers of nephrotoxicity through gene expression using gentamicin

Cinnabar protects serum-nutrient starvation induced apoptosis by improving intracellular oxidative stress and inhibiting the expression of CHOP and PERK

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