Importance of adenosine triphosphate in phospholipase A2-induced rabbit renal proximal tubule cell injury.

Abstract

The pathogenesis of ischemic renal tubular cell injury involves a complex interaction of different processes, including membrane phospholipid alterations and depletion of high-energy phosphate stores. To assess the role of membrane phospholipid changes due to activation of phospholipases in renal tubule cell injury, suspensions enriched in rabbit renal proximal tubule segments were incubated with exogenous phospholipase A2 (PLA2). Exogenous PLA2 did not produce any significant change in various metabolic parameters reflective of cell injury in control nonhypoxic preparations despite a significant decrease in phosphatidylethanolamine (PE) and moderate increases in lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE). In contrast, exogenous PLA2 treatment of hypoxic tubules resulted in a severe degree of cell injury, as demonstrated by marked declines in tubule K+ and ATP contents and significant decreases in tubule uncoupled respiratory rates, and was associated with significant phospholipid alterations, including marked declines in phosphatidylcholine (PC) and PE and significant rises in LPC, LPE, and free fatty acids (FFA). The injurious metabolic effects of exogenous PLA2 on hypoxic tubules were reversed by addition of ATP-MgCI2 to the tubules. The protective effect of ATPMgCl2 was associated with increases in tubule PC and PE contents and declines in LPC, LPE, and FFA contents. These experiments thus indicate that an increase in exogenous PLA2 activity produces renal proximal tubule cell injury when cell ATP levels decline, at which point phospholipid resynthesis cannot keep pace with phospholipid degradation with resulting depletion of phospholipids and accumulation of lipid by-products. High-energy phosphate store depletion appears to be an important condition for exogenous PLA2 activity to induce renal tubule cell injury.

Sphingosine: a mediator of acute renal tubular injury and subsequent cytoresistance.

“…It has been widely suggested that phospholipase A2-generated phospholipid by-products, most notably fatty acids and lysophospholipids, participate in the evolution of acute renal tubular cell injury (12)(13)(14)(15)(16)(17). However, that sphingolipid metabolites/breakdown products have potent signaling effects raises the possibility that they, too, could be involved.…”

“…A characteristic feature of acute toxic and ischemic renal tubular cell injury is partial degradation of membrane lipid constituents, leading to the accumulation of lipid by-products (12)(13)(14)(15)(16)(17). This suggests that the sphingomyelinase/ceramide/ sphingosine pathway could be involved in acute cell injury and repair.…”

“…As examples, ceramide can inhibit cellular proliferation, induce differentiation, inhibit protein trafficking/secretion, and trigger apoptotic cell death (1-4). That these effects are likely mediated by secondary phosphorylation events (5-7) and that selected cytokines/hormones activate sphingomyelinases suggest that a ceramide/sphingosine signaling pathway exists (8-11).A characteristic feature of acute toxic and ischemic renal tubular cell injury is partial degradation of membrane lipid constituents, leading to the accumulation of lipid by-products (12)(13)(14)(15)(16)(17). This suggests that the sphingomyelinase/ceramide/ sphingosine pathway could be involved in acute cell injury and repair.…”

Role of cytosolic calcium-independent plasmalogen-selective phospholipase A2 in hypoxic injury to rabbit proximal tubules.

“…Activation of intracellular phospholipase A2 (PLA2)' has been implicated as an important biochemical mechanism responsible for accelerated phospholipid hydrolysis during renal ischemia (1)(2)(3)(4)(5). The vast majority of previous studies of the PLA2 1. Abbreviations used in this paper: AA, arachidonic acid; Compound 1, 1-3-(E)-6-(bromomethylene)-(tetrahydro-3-( 1-naphthalenyl)-2H-pyran-2-one; LDH, lactate dehydrogenase; PLA2, phospholipase A2.…”

Subcellular characteristics of phospholipase A2 activity in the rat kidney. Enhanced cytosolic, mitochondrial, and microsomal phospholipase A2 enzymatic activity after renal ischemia and reperfusion.

“…Our previously reported data led us to conclude that PLA2 activation, consequent to calcium and reactive oxygen species exposure during reoxygenation, played an important role in electron transport chain damage localized to NADH coenzyme Q reductase, decreased F,-ATPase activity, decreased ADP-ATP translocase activity, and increased mitochondrial membrane permeability to H+ ions (3,6). Exogenous PLA2 treatment of hypoxic proximal tubules results in severe cellular injury and significant decreases in uncoupled respiratory rates of the tubules, reflective of electron transport chain damage (9).…”