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Tenofovir Toxicity Targets Mitochondria of Renal Proximal Tubules
Author(s) -
Kohler James John,
Hosseini Seyed,
HoyingBrandt Amy,
Green Elgin,
Tran Dung,
Russ Rodney,
Santoianni Robert,
Lewis William
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.739.23
Subject(s) - mitochondrial toxicity , toxicity , kidney , mitochondrion , didanosine , tenofovir , mitochondrial dna , biology , laser capture microdissection , medicine , reverse transcriptase , pharmacology , endocrinology , chemistry , pathology , biochemistry , virology , human immunodeficiency virus (hiv) , rna , viral load , antiretroviral therapy , gene expression , gene
Tenofovir disoproxil fumarate (TDF) is an analog of adenosine monophosphate that inhibits HIV reverse transcriptase in HIV/AIDS. Despite its therapeutic success, renal tubular side effects are reported. Mechanisms and targets of TDF toxicity were determined using "2 by 2" factorial protocols that included HIV transgenic mice (TG) and wild‐type (WT) littermates with or without oral TDF (5 weeks). A parallel study employed didanosine (ddI) instead of TDF. At termination, heart, kidney and liver samples were retrieved. Laser‐capture microdissection (LCM) isolated renal proximal tubules for molecular analyses. Mitochondrial DNA (mtDNA) abundance, histo‐ and ultrastructural pathology were analyzed. TDF increased mtDNA abundance in TG whole‐kidneys, but not hearts or livers. In contrast, ddI decreased mtDNA abundance in livers of WTs and TGs, but had no effect on hearts or kidneys. LCM‐captured renal proximal tubules from TGs exhibited decreased mtDNA abundance with TDF. Histological analyses of kidneys showed no disruption of glomeruli or proximal tubules with TDF or ddI treatments. Ultrastructural features in renal proximal tubules from TDF treated TGs included increased number and irregular shaped mitochondria with sparse fragmented cristae. Results indicate tissue‐specific toxicity from TDF and ddI monotherapies. TDF toxicity targets mitochondrial renal proximal tubules in an AIDS model.