Organic solvent-induced proximal tubular cell toxicity via caspase-3 activation.
BACKGROUND
Occupational exposure to solvents may be associated with development and progression of tubulo-interstitial fibrosis and chronic renal failure. However, the cellular mechanisms by which this occurs remain elusive.


METHODS
The cytotoxicity of proximal tubular cells (LLC-PK1) exposed to 106 mg/mL of p-xylene or 92 mg/mL of toluene was compared with untreated controls using cell viability (MTS assay) and caspase-3 activity, with or without caspase-3 selective inhibitor.


RESULTS
Both compounds reduced cell viability and increased caspase-3 activation (P < 0.005). Inhibition of caspase-3 by the selective inhibitor DEVD-CHO prevented injury (P < 0.001) and inhibited solvent-induced caspase-3 activation (P < 0.005).


CONCLUSIONS
Inhibition of caspase-3, the critical caspase in the apoptosis process, prevents cell injury in LLC-PK1. This suggests that caspase-3 may play a pivotal role in solvent-induced proximal tubular cell injury.
Al-Ghamdi
Saeed S
SS
Department of Experimental Medicine and Nephrology, St. Bart's and Royal London School of Medicine and Dentistry, Queen Mary-University of London, London, UK. s_alghamdi@go.com
Raftery
Martin J
MJ
Yaqoob
Muhammad M
MM
D000818:Animals; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D009842:Oligopeptides / Q000494:pharmacology; D012997:Solvents / Q000633:toxicity*; D013552:Swine; D014050:Toluene / Q000633:toxicity*; D014992:Xylenes / Q000633:toxicity*
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D012997:Solvents; D014992:Xylenes; C108637:aspartyl-glutamyl-valyl-aspartal; D014050:Toluene; C031286:4-xylene; D053148:Caspase 3; D020169:Caspases