Journal of the American Society of Nephrology, Vol 7, 2327-2339, Copyright © 1996 by American Society of Nephrology

REGULAR ARTICLES

Phospholipase A2: a potentially important determinant of adenosine triphosphate levels during hypoxic-reoxygenation tubular injury

RA Zager, DS Conrad and K Burkhart
Department of Medicine, University of Washington, Seattle, USA.

During the course of O2 deprivation-induced proximal tubular injury, profound alterations in ATP homeostasis exist. This study sought to characterize direct cellular determinants of these abnormalities further. Mouse proximal tubular segments (PTS) were isolated and their adenine nucleotide profiles were determined during hypoxic- reoxygenation injury. The extent of oxidant stress, Ca2+ overload, cytoskeletal disruption, and phospholipase activity were experimentally manipulated by H2O2, Ca2+ ionophore, cytochalasin D, or PLA2 addition, respectively. Hypoxia induced the expected deterioration in adenylate profiles, and a persistent defect in ATP homeostasis was observed during reoxygenation (decreased ATP/ADP ratios and absolute ATP content). H2O2, Ca2+ ionophore, and cytochalasin D had no significant impact on adenylate profiles. However, doses of PLA2 that had no overt effect on normal tubules caused 50 to 75% reductions in both hypoxic and reoxygenation ATP/ADP ratios and absolute ATP content. This effect was completely reproduced by the addition of arachidonic acid (C20:4). No other test fatty acid (C16:0, C18:1, C18:3) reproduced this result. Despite its profound negative impact on hypoxic/reoxygenation ATP concentrations, PLA2 and C20:4 each decreased lethal cell injury (lactate dehydrogenase release), as previously reported. The reductions in ATP and lethal cell injury were not mechanistically linked, because C18:1 and C18:3 reproduced the protective action of C20:4 without altering adenine nucleotide profiles. Ouabain, mannitol, or plasma membrane fatty acid "scavenger" therapy (albumin) did not improve the posthypoxic/PLA2-induced depressions in ATP. The addition of C20:4 caused a modest decrease in posthypoxic tubule oxygen consumption, compared to controls. It was concluded that: (1) PLA2 can be a major determinant of ATP concentrations during both hypoxic and reoxygenation tubular injury; (2) this action is mediated via C20:4 release; (3) a primary defect in mitochondrial ATP production, rather than increased ATP consumption, is likely to be responsible for this action.

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