Tenofovir renal toxicity targets mitochondria of renal proximal tubules.
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. The mechanisms and targets of tenofovir toxicity were determined using '2 x 2' factorial protocols, and HIV transgenic (TG) and wild-type (WT) littermate mice with or without TDF (5 weeks). A parallel study used didanosine (ddI) instead of TDF. At termination, heart, kidney, and liver samples were retrieved. Mitochondrial DNA (mtDNA) abundance, and histo- and ultrastructural pathology were analyzed. Laser-capture microdissection (LCM) was used to isolate renal proximal tubules for molecular analyses. Tenofovir increased mtDNA abundance in TG whole kidneys, but not in their hearts or livers. In contrast, ddI decreased mtDNA abundance in the livers of WTs and TGs, but had no effect on their hearts or kidneys. Histological analyses of kidneys showed no disruption of glomeruli or proximal tubules with TDF or ddI treatments. Ultrastructural changes in renal proximal tubules from TDF-treated TGs included an increased number and irregular shape of mitochondria with sparse fragmented cristae. LCM-captured renal proximal tubules from TGs showed decreased mtDNA abundance with tenofovir. The results indicate that tenofovir targets mitochondrial toxicity on the renal proximal tubule in an AIDS model.
Kohler
James J
JJ
Department of Pathology, Emory University, Atlanta, GA 30322, USA. jjkohle@emory.edu
Hosseini
Seyed H
SH
Hoying-Brandt
Amy
A
Green
Elgin
E
Johnson
David M
DM
Russ
Rodney
R
Tran
Dung
D
Raper
C Michael
CM
Santoianni
Robert
R
Lewis
William
W
D016263:AIDS-Associated Nephropathy / Q000139:chemically induced* / Q000473:pathology; D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives*; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects*; D004272:DNA, Mitochondrial / Q000378:metabolism; D016049:Didanosine / Q000009:adverse effects; D005260:Female; D015497:HIV-1; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D042282:Microdissection; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D063065:Organophosphonates / Q000009:adverse effects*; D000068698:Tenofovir; D019459:Urothelium / Q000648:ultrastructure
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine; D016049:Didanosine