Statins inhibit aminoglycoside accumulation and cytotoxicity to renal proximal tubule cells.
Nephrotoxicity due to renal proximal tubule accumulation of aminoglycoside (AG) antibiotics, such as gentamicin, represents a major clinical problem. Receptor-mediated endocytosis via the multi-ligand receptor megalin is thought to be a key mechanism in the cellular uptake of AGs and nephrotoxicity. This process can be modulated by the intracellular concentration of isoprenoid pyrophosphates derived from the processing of mevalonate by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Post-translation modifications by isoprenoid pyrophosphates are necessary for GTP-binding protein function. Given that statins inhibit HMG-CoA reductase and therefore affect the concentration of isoprenoid pyrophosphates, we have tested the hypothesis that statins will lead to a reduction in AG renal proximal tubule accumulation and cytotoxicity. Gentamicin accumulated within cultured proximal tubule derived opossum kidney (OK) cells and led to dose- and time-dependent cell death which was inhibited by non-toxic doses of simvastatin (IC(50) 1.3 microM), rosuvastatin (IC(50) 16.3 microM) and pravastatin (IC(50) 38.8 microM). The mechanism of inhibition was linked to the degree of cholesterol synthesis inhibition and GTP-binding protein unprenylation. Moreover, co-incubation with mevalonate or geranyl-geranyl pyrophosphate, products of HMG-CoA reductase, reversed the inhibitory effect of statins on cellular accumulation and cytotoxicity of gentamicin. In summary, our data suggest that the inhibition of the mevalonate pathway by statins may provide a potential therapeutic strategy to prevent AG-induced nephrotoxicity.
Antoine
Daniel J
DJ
MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, University of Liverpool, Merseyside, L69 3GE, UK. d.antoine@liv.ac.uk
Srivastava
Abhishek
A
Pirmohamed
Munir
M
Park
B Kevin
BK
D000617:Aminoglycosides / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009893:Opossums
D000617:Aminoglycosides; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors