Tenofovir renal proximal tubular toxicity is regulated By OAT1 and MRP4 transporters

Tenofovir disoproxil fumarate (TDF) is an oral prodrug and acyclic nucleotide analog of adenosine monophosphate that inhibits HIV-1 (HIV) reverse transcriptase. A growing subset of TDF-treated HIV+ individuals presented with acute renal failure, suggesting tenofovir-associated kidney-specific toxici...

Full description

Saved in:
Bibliographic Details
Published in:Laboratory investigation 2011-06, Vol.91 (6), p.852-858
Main Authors: Kohler, James J, Hosseini, Seyed H, Green, Elgin, Abuin, Allison, Ludaway, Tomika, Russ, Rodney, Santoianni, Robert, Lewis, William
Format: Article
Language:English
Subjects:
Adenine - administration & dosage
Adenine - analogs & derivatives
Adenine - toxicity
Analysis of Variance
Animals
antiretrovirals
Biological and medical sciences
Biotechnology
DNA, Mitochondrial - metabolism
Fundamental and applied biological sciences. Psychology
Investigative techniques, diagnostic techniques (general aspects)
Kidney Tubules, Proximal - drug effects
Kidney Tubules, Proximal - metabolism
Kidney Tubules, Proximal - pathology
knockout mice
Lasers
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Microdissection
Mitochondria - pathology
mitochondrial toxicity
mouse animal models
mtDNA
Multidrug Resistance-Associated Proteins - genetics
Multidrug Resistance-Associated Proteins - metabolism
Organic Anion Transport Protein 1 - genetics
Organic Anion Transport Protein 1 - metabolism
Organophosphonates - administration & dosage
Organophosphonates - toxicity
Reverse Transcriptase Polymerase Chain Reaction
Tenofovir
transporters
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Tenofovir disoproxil fumarate (TDF) is an oral prodrug and acyclic nucleotide analog of adenosine monophosphate that inhibits HIV-1 (HIV) reverse transcriptase. A growing subset of TDF-treated HIV+ individuals presented with acute renal failure, suggesting tenofovir-associated kidney-specific toxicity. Our previous studies using an HIV transgenic mouse model (TG) demonstrated specific changes in renal proximal tubular mitochondrial DNA (mtDNA) abundance. Nucleosides are regulated in biological systems via transport and metabolism in cellular compartments. In this study, the role(s) of organic anion transporter type 1 (OAT1) and multidrug-resistant protein type 4 (MRP4) in transport and regulation of tenofovir in proximal tubules were assessed. Renal toxicity was assessed in kidney tissues from OAT1 knockout (KO) or MRP4 KO compared with wild-type (WT, C57BL/6) mice following treatment with TDF (0.11 mg/day), didanosine (ddI, a related adenosine analog, 0.14 mg/day) or vehicle (0.1 M NaOH) daily gavage for 5 weeks. Laser-capture microdissection (LCM) was used to isolate renal proximal tubules for molecular analyses. mtDNA abundance and ultrastructural pathology were analyzed. mtDNA abundance in whole kidneys from both KO and WT was unchanged regardless of treatment. Renal proximal tubular mtDNA abundance from OAT1 KO also remained unchanged, suggesting prevention of TDF toxicity due to loss of tenofovir transport into proximal tubules. In contrast, renal proximal tubules from MRP4 KO exhibited increased mtDNA abundance following TDF treatment compared with WT littermates, suggesting compensation. Renal proximal tubules from TDF-treated WT and MRP4 KO exhibited increased numbers of irregular mitochondria with sparse, fragmented cristae compared with OAT1 KO. Treatment with ddI had a compensatory effect on mtDNA abundance in OAT1 KO but not in MRP4 KO. Both OAT1 and MRP4 have a direct role in transport and efflux of tenofovir, regulating levels of tenofovir in proximal tubules. Disruption of OAT1 activity prevents tenofovir toxicity but loss of MRP4 can lead to increased renal proximal tubular toxicity. These data help to explain mechanisms of human TDF renal toxicity.
ISSN:0023-6837
1530-0307
DOI:10.1038/labinvest.2011.48