Phospholipase A2 activity can protect renal tubules from oxygen deprivation injury.
During hypoxic or ischemic renal tubular injury, phospholipase A2 (PLA2) induces membrane deacylation, causing fatty acid accumulation and phospholipid breakdown. Because these changes can compromise cellular integrity, PLA2 activity has been widely proposed as a critical mediator of hypoxic renal tubular injury and, hence, of ischemic acute renal failure. To explore this hypothesis, isolated rat proximal tubules were subjected to continuous oxygenation or to hypoxic injury with or without exogenous PLA2 addition (porcine or bovine pancreatic PLA2; bee or snake venom PLA2). Cell death was quantified by lactic dehydrogenase (LDH) release. Pancreatic PLA2 (0.4 unit/ml) caused no LDH release under oxygenated conditions, and it dramatically attenuated hypoxic cell death (e.g., no PLA2, 55 +/- 3% LDH release; porcine pancreatic PLA2, 22 +/- 1% LDH release; P < 0.001). Bee and snake venom PLA2 (0.4 unit/ml) were directly toxic to tubules under oxygenated conditions, and this injury was additive with that induced by hypoxia. However, when these venoms were serially diluted (removing their overt toxicity), they, too, mitigated hypoxic cell death (LDH release with PLA2, 33 +/- 2%; without PLA2, 60 +/- 1% LDH release; P < 0.001). PLA2-mediated cytoprotection was Ca2+ dependent (negated by Ca2+ chelation), and it was expressed despite worsening hypoxia-associated membrane deacylation/fatty acid accumulation (12 times) and ATP depletion. These results indicate that PLA2 activity can exert both beneficial and deleterious effects on O2-deprived renal tubules, the net result of which can be a salvaging of cells from hypoxic cell death.
Zager
R A
RA
Fred Hutchinson Cancer Research Center, University of Washington, Seattle 98104.
Schimpf
B A
BA
Gmur
D J
DJ
Burke
T J
TJ
D000227:Adenine Nucleotides / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D004533:Egtazic Acid / Q000494:pharmacology; D004734:Energy Metabolism; D005227:Fatty Acids / Q000032:analysis; D000860:Hypoxia; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008297:Male; D010179:Pancreas / Q000201:enzymology; D010741:Phospholipases A / Q000494:pharmacology*; D054467:Phospholipases A2; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
D000227:Adenine Nucleotides; D005227:Fatty Acids; D004533:Egtazic Acid; D007770:L-Lactate Dehydrogenase; D010741:Phospholipases A; D054467:Phospholipases A2; D002118:Calcium