Tenofovir Renal Proximal Tubular Toxicity Is Regulated By OAT1 and MRP4 Transporters

• Type of Material: Article
• Authors: James J Kohler, Emory University; Seyed H. Hosseini, Emory University; Elgin Green, Emory University; Allison Abuin, Emory University; Tomika Ludaway, Emory University; Rodney Russ, Emory University; Robert Santoianni, Emory University; William Lewis, Emory University
• Language: English
• Date: 2011-06
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 USCAP, Inc All rights reserved
• Final Published Version (URL): http://www.nature.com/labinvest/journal/v91/n6/full/labinvest201148a.html
• Title of Journal or Parent Work: Laboratory Investigation
• ISSN: 0023-6837
• Volume: 91
• Issue: 6
• Start Page: 852
• End Page: 858
• Grant/Funding Information: National Heart, Lung, and Blood Institute : NHLBI; National Institute on Drug Abuse : NIDA; The studies were supported by a grant from Emory University Research Committee (URC) to JJK and R01 HL059798, HL079867 and DA030996 to WL. JJK is a recipient of K01 DK078513.
• Research Categories: Health Sciences, Pathology

Abstract

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 knock-out (KO) or MRP4 KO compared to 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 wks. 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 to 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 to 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 explain mechanisms of human TDF renal toxicity.