Mitochondrial tubulopathy in tenofovir disoproxil fumarate-treated rats

TY - JOUR

T1 - Mitochondrial tubulopathy in tenofovir disoproxil fumarate-treated rats

AU - Lebrecht, Dirk

AU - Venhoff, Ana C

AU - Kirschner, Janbernd

AU - Wiech, Thorsten

AU - Venhoff, Nils

AU - Walker, Ulrich A

PY - 2009/7/1

Y1 - 2009/7/1

N2 - OBJECTIVES: 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.METHODS: 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.RESULTS: 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%).CONCLUSIONS: 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.

AB - OBJECTIVES: 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.METHODS: 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.RESULTS: 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%).CONCLUSIONS: 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.

KW - Adenine

KW - Animals

KW - Anti-HIV Agents

KW - DNA, Mitochondrial

KW - Didanosine

KW - Electron Transport

KW - Electron Transport Complex IV

KW - Kidney Tubules, Proximal

KW - Male

KW - Microscopy, Electron, Transmission

KW - Mitochondria

KW - Mitochondrial Diseases

KW - NADH Dehydrogenase

KW - Organophosphonates

KW - Rats

KW - Rats, Sprague-Dawley

KW - Reverse Transcriptase Inhibitors

M3 - SCORING: Journal article

C2 - 19582894

VL - 51

SP - 258

EP - 263

JO - JAIDS-J ACQ IMM DEF

JF - JAIDS-J ACQ IMM DEF

SN - 1525-4135

IS - 3

ER -