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Mitochondrial dysfunction in S‐(1,2‐dichlorovinyl)‐L‐cysteine (DCVC)‐induced apoptosis and necrosis in human proximal tubular cells
Author(s) -
Lash Lawrence Harold,
Papanayotou Irene,
Putt David A.,
Xu Feng
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1138
Subject(s) - apoptosis , necrosis , mitochondrial permeability transition pore , programmed cell death , mitochondrion , biology , incubation , metabolite , microbiology and biotechnology , biochemistry , genetics
Confluent, primary cultures of human proximal tubular (hPT) cells were used to determine the relationship between mitochondrial dysfunction and cell death induced by DCVC, a nephrotoxic metabolite of trichloroethylene. Previous studies showed that DCVC causes cellular necrosis only at relatively high doses (> 100 μM) and long incubation times (> 24 hr) whereas both apoptosis and enhanced cellular proliferation occur at relatively low doses (10–100 μM) and early incubation times (2–8 hr). hPT cells were preincubated for 30 min with cyclosporin A (CsA), an inhibitor of the mitochondrial permeability transition. DCVC caused a modest, time‐ and dose‐dependent increase in apoptosis. CsA prevented the increase in apoptosis with 10 or 50 μM DCVC but increased apoptosis with 100 μM DCVC. Necrosis was only observed in cells incubated with 100 μM DCVC for 24 hr, and was diminished by CsA. CsA also prevented decreases in membrane potential and cellular concentrations of ATP. Thus, mitochondrial dysfunction plays a central role in controlling the response of hPT cells to DCVC and inhibition of the mitochondrial permeability transition shifts this response from necrosis to apoptosis at relatively high doses of DCVC or from apoptosis to protection at relatively low doses of DCVC. Supported by NIH Grant ES08828.