No abstract

Severe and recurrent cisplatin-induced acute kidney injury (AKI) as part of standard cancer therapy is a known risk factor for development of chronic kidney disease (CKD). The specific role of superoxide (O2•-)-mediated disruption of mitochondrial oxidative metabolism in CKD after cisplatin treatment is unexplored. Cisplatin is typically administered in weekly or tri-weekly cycles as part of standard cancer therapy. To investigate the role of O2•- in predisposing patients to future renal injury and in CKD, mice were treated with cisplatin and a mitochondrial-specific, superoxide dismutase (SOD) mimetic, GC4419. Renal function, biomarkers of oxidative stress, mitochondrial oxidative metabolism, and kidney injury markers, as well as renal histology, were assessed to evaluate the cellular changes that occur one week and one month (CKD phase) after the cisplatin insult. Cisplatin treatment resulted in persistent upregulation of kidney injury markers, increased steady-state levels of O2•-, increased O2•--mediated renal tubules damage, and upregulation of mitochondrial electron transport chain (ETC) complex I activity both one week and one month following cisplatin treatment. Treatment with a novel, clinically relevant, small-molecule superoxide dismutase (SOD) mimetic, GC4419, restored mitochondrial ETC complex I activity to control levels without affecting complexes II–IV activity, as well as ameliorated cisplatin-induced kidney injury. These data support the hypothesis that increased mitochondrial O2•- following cisplatin administration, as a result of disruptions of mitochondrial metabolism, may be an important contributor to both AKI and CKD progression.

No abstract

Phospholipase A(2) (PLA(2))-catalyzed hydrolysis of membrane phospholipids results in the stoichiometric production of a free fatty acid, most importantly arachidonic acid, and a lysophospholipid. Both of these phospholipid metabolites serve as precursors for inflammatory mediators such as eicosanoids or platelet-activating factor (PAF). Since it was initially discovered that non-steroidal anti-inflammatory drugs inhibit prostaglandin synthesis, a vast amount of drug development has been performed to selectively inhibit the production of the inflammatory metabolites of arachidonic acid while preserving their protective role. This research has culminated in the development of selective cyclooxygenase-2 (COX-2) inhibitors that act on the inducible, inflammatory COX enzyme, but do not affect the constitutive prostaglandin synthesis in cells that is mediated via COX-1. The development of PLA(2) inhibitors as potential anti-inflammatory agents has also been extensively pursued since the release of arachidonic acid from membrane phospholipids by PLA(3) is one of the rate-limiting factors for eicosanoid production. In addition to the production of eicosanoids, PLA(2)-catalyzed membrane phospholipid hydrolysis is also the initiating step in the generation of PAF, a potent inflammatory agent. Thus, inhibition of PLA(2) activity should, in theory, be a more effective anti-inflammatory approach. However, developing an inhibitor that would be selective for the production of inflammatory metabolites and not inhibit the beneficial properties of PLA(2) has so far proved to be elusive. This review will focus on agents used currently to inhibit PLA(2) activity and will explore their possible therapeutic use.

Glial fibrillary acid protein (GFAP)-positive astrocytes isolated from the cerebral cortices of 3-10-dayold rats frequently showed increased intracellular Ca 2c oncentration responses to L-glutamate and glutamate analogues. However, few of the acutely isolated cells responded to ATP, and no such cells responded to serotonm [5-hydroxytryptamine(5-HT)]. The same cell that failed to respond to ATP or 5-HT often responded to glutamate. Culturing acutely isolated cells in media containing horse serum decreased Ca2~responses to glutamate but increased the responses to ATP and induced responses to 5-HT. In primary cultures prepared from the cerebral cortices of 1-day-old rats and cultured in horse serum, fewer of the cells responded to glutamate, but almost all cells responded to ATP and 5-HT. The lack of, or limited response to, 5-HT or ATP in the acutely isolated cells seems unlikely to be due to selective damage to the respective receptors because acutely isolated GFAPnegative cells showed responses to ATP, several different proteases and mechanical dissociation yielded cells that also responded to glutamate but not to ATP, and exposure of primary cultures to papain did not abolish Ca2r esponses to several transmitters. The responses of the acutely isolated cells to glutamate but limited or lack of responses to ATP and 5-HT also correspond to what has been seen so far for astrocytes in situ. Thus, the present studies provide direct evidence that some of the receptors seen in primary astrocyte cultures may reflect a response to culture conditions and that, in the context of the relevant information so far available, acutely isolated astrocytes seem to reflect better the in vivo state.