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Tenofovir-induced toxicity in renal proximal tubular epithelial cells: involvement of mitochondria.

Tenofovir-induced toxicity in renal proximal tubular epithelial cells: involvement of mitochondria.
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Milián L, Peris JE, Gandía P, Andújar I, Pallardó L, Górriz JL, Blas-García A,


Milián L, Peris JE, Gandía P, Andújar I, Pallardó L, Górriz JL, Blas-García A, (click to view)

Milián L, Peris JE, Gandía P, Andújar I, Pallardó L, Górriz JL, Blas-García A,

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AIDS (London, England) 31(12) 1679-1684 doi 10.1097/QAD.0000000000001572

Abstract
OBJECTIVE
In-vivo studies suggest that mitochondria is involved in tenofovir (TFV)-induced renal toxicity, but the underlying mechanisms are still unclear. The aim of the present study was to assess the effects of TFV and its prodrug, TFV disoproxil fumarate, on mitochondrial function and cell survival/viability in a renal proximal tubular cell line.

DESIGN AND METHODS
We evaluated parameters of cellular proliferation/survival (cell count, cell cycle, viability) and mitochondrial function (oxygen consumption, mitochondrial membrane potential, reactive oxygen species production) in NRK-52E cells. Intracellular TFV was measured by HPLC and expression of antioxidant genes was analysed by real-time PCR.

RESULTS
Similar intracellular levels of TFV were reached with lower concentrations of the prodrug than of the drug, and correlated directly with a decrease in cell number. Both compounds inhibited proliferation and compromised mitochondrial function by decreasing mitochondrial membrane potential and increasing oxygen consumption and mitochondrial superoxide production. Altered oxidative status was confirmed by the overexpression of antioxidant genes.

CONCLUSIONS
Intracellular accumulation of TFV induces mitochondrial toxicity in an in-vitro renal model and alters cell proliferation and viability. Our findings call for caution regarding the use of this nucleotide analogue reverse transcriptase inhibitor in patients with other risk factors that compromise mitochondrial function in the kidney.

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