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Mitochondrial Tubulopathy in Tenofovir Disoproxil Fumarate-Treated Rats
- Source :
- JAIDS Journal of Acquired Immune Deficiency Syndromes. 51:258-263
- Publication Year :
- 2009
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2009.
-
Abstract
- Tenofovir disoproxil fumarate (tenofovir DF) use has been associated with renal dysfunction and Fanconi syndrome. Tenofovir is taken up into renal tubules by anion transporters where high intracellular drug concentration may induce a functionally relevant depletion of mitochondrial DNA (mtDNA). We investigated if tenofovir may induce renal mtDNA depletion and respiratory chain dysfunction.Rats (n = 8) were gavaged daily with 100 mg x kg(-1) x d(-1) of tenofovir DF or didanosine. Kidneys and livers were examined after 8 weeks of treatment.The tenofovir group had significantly lower body and kidney weights than rats exposed to water or didanosine. Proximal but not distal tubules were of increased diameter and contained small lipid droplets. Tubular mitochondria were enlarged, and their crystal architecture was disrupted. Tenofovir-exposed kidneys contained low mtDNA copy numbers and impaired expression of mtDNA-encoded cytochrome c oxidase (COX) I but not nucleus-encoded COX IV subunits. Histochemistry demonstrated low tubular COX and nicotinamide adenine dinucleotide dehydrogenase (NADH-DH) activities, whereas succinate dehydrogenase activity was preserved. COX activity was preserved in the glomeruli of tenofovir-exposed rats. Didanosine did not elicit renal effects but, unlike tenofovir, depleted mtDNA in liver (by 52%).Tenofovir DF induces an organ-specific nephrotoxicity with mtDNA depletion and dysfunction of mtDNA-encoded respiratory chain subunits. The data do not support nephrotoxicity of didanosine.
- Subjects :
- Male
medicine.medical_specialty
Mitochondrial DNA
Mitochondrial Diseases
Anti-HIV Agents
Organophosphonates
Mitochondrion
Biology
urologic and male genital diseases
DNA, Mitochondrial
Nephrotoxicity
Electron Transport
Electron Transport Complex IV
Kidney Tubules, Proximal
Rats, Sprague-Dawley
Microscopy, Electron, Transmission
Tubulopathy
immune system diseases
Internal medicine
medicine
Animals
Pharmacology (medical)
Tenofovir
Kidney
Adenine
virus diseases
Fanconi syndrome
NADH Dehydrogenase
medicine.disease
Mitochondria
Rats
Didanosine
Mitochondrial toxicity
Infectious Diseases
Endocrinology
medicine.anatomical_structure
Reverse Transcriptase Inhibitors
Kidney disease
Subjects
Details
- ISSN :
- 15254135
- Volume :
- 51
- Database :
- OpenAIRE
- Journal :
- JAIDS Journal of Acquired Immune Deficiency Syndromes
- Accession number :
- edsair.doi.dedup.....75a37ea313c821e4bd0c32cf57fb6ff1
- Full Text :
- https://doi.org/10.1097/qai.0b013e3181a666eb