Rosiglitazone reverses tenofovir-induced nephrotoxicity.
Tenofovir disoproxil fumarate (TDF) is a first-line drug used in patients with highly active retroviral disease; however, it can cause renal failure associated with many tubular anomalies that may be due to down regulation of a variety of ion transporters. Because rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist induces the expression of many of these same transporters, we tested if the nephrotoxicity can be ameliorated by its use. High doses of TDF caused severe renal failure in rats accompanied by a reduction in endothelial nitric-oxide synthase and intense renal vasoconstriction; all of which were significantly improved by rosiglitazone treatment. Low-dose TDF did not alter glomerular filtration rate but produced significant phosphaturia, proximal tubular acidosis, polyuria and a reduced urinary concentrating ability. These alterations were caused by specific downregulation of the sodium-phosphorus cotransporter, sodium/hydrogen exchanger 3 and aquaporin 2. A Fanconi's-like syndrome was ruled out as there was no proteinuria or glycosuria. Rosiglitazone reversed TDF-induced tubular nephrotoxicity, normalized urinary biochemical parameters and membrane transporter protein expression. These studies suggest that rosiglitazone treatment might be useful in patients presenting with TFV-induced nephrotoxicity especially in those with hypophosphatemia or reduced glomerular filtration rate.
Libório
Alexandre B
AB
Laboratory of Basic Science, Department of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil.
Andrade
Lúcia
L
Pereira
Leonardo V B
LV
Sanches
Talita R C
TR
Shimizu
Maria H
MH
Seguro
Antonio C
AC
D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives*; D000818:Animals; D064420:Drug-Related Side Effects and Adverse Reactions / Q000188:drug therapy; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D017674:Hypophosphatemia / Q000188:drug therapy; D007015:Hypophosphatemia, Familial / Q000188:drug therapy; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D026901:Membrane Transport Proteins / Q000187:drug effects; D063065:Organophosphonates / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects; D000077154:Rosiglitazone; D000068698:Tenofovir; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*
D007004:Hypoglycemic Agents; D026901:Membrane Transport Proteins; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000068698:Tenofovir; D000225:Adenine