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Mitochondrial Tubulopathy in Tenofovir Disoproxil Fumarate-Treated Rats

Authors :
Janbernd Kirschner
Nils Venhoff
Ana C Venhoff
Thorsten Wiech
Dirk Lebrecht
Ulrich A. Walker
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.

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