Subcellular Renal Proximal Tubular Mitochondrial Toxicity with Tenofovir Treatment
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.
Key wordsNRTIs TDF Renal proximal tubules Mitochondrial toxicity Renal disease Transgenic mice mtDNA abundance
The authors would like to thank Professor William Lewis (WL) for his advice and support and Dianne Alexis in the Pathology Core Laboratory for assistance in the histological staining and tissue section protocols. This work was supported by R01 HL79867 to WL; JK is a recipient of K01 DK78513.
- 11.Cote, H. C., Magil, A. B., Harris, M., et al. (2006) Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral therapy. Antivir Ther 11: 79–86.Google Scholar