Subcellular Renal Proximal Tubular Mitochondrial Toxicity with Tenofovir Treatment

Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs) are drugs used in the treatment of HIV/AIDS. Despite the distinct benefits of NRTI-based therapies, tissue specific toxicity is a limiting factor. Although the mechanisms of these specific antiretroviral drug-related toxicities remain unclear, it has been hypothesized that as analogs to native nucleosides, NRTIs may potentially inhibit mammalian DNA polymerases, including mitochondrial DNA (mtDNA) polymerase γ. Tenofovir disoproxil fumarate (TDF) is a nucleotide analog of adenosine monophosphate and the only NRTI that is associated with renal disease. The inherent heterogeneity of kidney tissues could affect the outcome and interpretation of molecular studies to define the mechanism(s) of tenofovir tubular toxicity. Laser-capture microdissection (LCM) provided a specific, single-cell isolation of proximal tubules from fixed heterogeneous kidney tissues. LCM-captured renal proximal tubules from transgenic mice (TGs) showed decreased mtDNA abundance with tenofovir, demonstrating a subcellular specific mitochondrial toxicity of tenofovir in an AIDS model.