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OAT1 Knock‐out Mice Define Its Role in Tenofovir Transport and Renal Proximal Tubular Mitochondrial Toxicity
Author(s) -
Kohler James J,
Hosseini Seyed H,
Green Elgin,
Russ Rodney,
Santoianni Robert,
Lewis William
Publication year - 2010
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.24.1_supplement.1030.1
Subject(s) - kidney , mitochondrion , toxicity , laser capture microdissection , reverse transcriptase , chemistry , mitochondrial dna , tenofovir , genetically modified mouse , organic anion transporter 1 , transporter , mitochondrial toxicity , medicine , endocrinology , biology , pharmacology , microbiology and biotechnology , transgene , biochemistry , virology , rna , human immunodeficiency virus (hiv) , gene , gene expression
Tenofovir disoproxil fumarate (TDF) is an analog of adenosine monophosphate that inhibits HIV reverse transcriptase. Despite its therapeutic success, renal side effects exist. The role of organic anion transporter 1 (OAT1) in secretion of TDF was determined using OAT1 knock‐out (KO) and wild‐type (WT) with or without TDF (5 week dose). Laser‐capture microdissection (LCM) isolated renal proximal tubules from kidney samples for molecular analyses. Mitochondrial DNA (mtDNA) abundance and ultrastructural pathology were analyzed. mtDNA abundance in KO and WT whole‐kidneys were unchanged regardless of treatment. Renal proximal tubules from KOs also exhibited no change following TDF treatment compared to previous findings in HIV transgenic mice (TG) which exhibited decreased mtDNA abundance. Renal proximal tubules from TDF treated WTs, but not KOs, exhibited increased numbers of irregularly shaped mitochondria with sparse, fragmented cristae. OAT1 has a direct role in transport of TDF in the murine proximal tubules. These data help explain mechanisms of human TDF renal toxicity.