Fatty acid-induced cytotoxicity: differences in susceptibility between MDCK cells and primary cultures of proximal tubular cells.
We have compared the cytotoxicity of exogenously added fatty acid (oleic acid) and that of endogenous free fatty acids released from cell membranes by phospholipase A2 in primary cultures of mouse proximal tubular (MPT) cells and in Madine-Darby canine kidney (MDCK) cells. Exposure of MPT cell monolayers to oleic acid (125 mmol/L) for 2 hours resulted in severe irreversible injury to 70% +/- 4% of MPT cells. In striking contrast, only 8% +/- 3% of MDCK cells were killed by the same insult. This striking difference in the response to exogenous oleate by MPT and MDCK cells was associated with modest and comparable reductions in cell adenosine triphosphate (ATP) content in both cell types. Chemical anoxia induced by cyanide plus deoxyglucose (CN-DOG) in the absence of glucose was associated with greater injury in MPT cells (45% +/- 6% killed) than in MDCK cells (16% +/- 5% cells killed) despite severe and comparable depletion of cell ATP content in both MPT cells (96.0% +/- 0.6% reduction) and MDCK cells (96.0% +/- 0.5% reduction). The release of endogenous fatty acids by the exposure of cells to exogenous phospholipase A2 caused mild injury in both cell types that was more severe in MPT cells than in MDCK cells. The combined insult of phospholipase A2 and chemical anoxia for 2 hours caused substantially greater cell injury in both MPT and MDCK cells than either intervention alone, but the combined insult was still more damaging to MPT cells (73% +/- 4% killed) than to MDCK cells (30% +/- 4% killed). We conclude that the cell membrane in MDCK cells is intrinsically more resistant to fatty acid-induced injury than the lipid membrane in MPT cells.
Lieberthal
W
W
Evans Memorial Department of Clinical Research, Boston Medical Center, MA 02118, USA.
Sheridan
A M
AM
Schwartz
J H
JH
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003486:Cyanides / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D004285:Dogs; D004338:Drug Combinations; D004351:Drug Resistance; D005227:Fatty Acids / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology
D003486:Cyanides; D004338:Drug Combinations; D005227:Fatty Acids; D000255:Adenosine Triphosphate; D003847:Deoxyglucose