Several succininimide derivatives have been shown to induce renal damage (acute tubular necrosis, interstitial fibrosis) or bladder damage (hemorrhagic cystitis) in man and/or animals. The wide use of succinimide compounds with little understanding of the mechanisms by which this class of compounds can induce nephrotoxicity and bladder damage, indicates the need for mechanistic studies of succinimide- induced toxicity. This proposal will continue our studies to investigate the mechanism(s) of N- and C-arylsuccinimide-induced nephrotoxicity and urotoxicity. For N-arylsuccinimides, we will test the hypothesis that N-arylsuccinimides are biotransformed in the liver to sulfate and glucuronide conjugates which are carried by the blood to kidney where they accumulate. The conjugates then either release N-aryl maleimides which can alkylate renal macromolecules (e.g. mitochondrial proteins) or directly alkylate/acylate similar cellular targets. This hypothesis will be examined in four specific aims using the agricultural fungicide N- (3,5-dichlorophenyl) succinimide (NDPS) as the parent succinimide.
In Aim 1 we will identify the nephrotoxicant conjugate(s) of NDPS using in vivo and in vitro models.
Aim 2 will examine the cellular mechanism of NDPS nephrotoxicity (effects on cell calcium, ATP production oxygen consumption) using isolated renal proximal tubule epithelial cells and isolated renal cortical mitochondria.
In Aim 3, we will investigate renal cellular localization and potential cellular targets for NDPS using immunohistochemical and immunochemical techniques to complement studies in Aims 1 and 2, while in Aim 4 we will begin to investigate how toxic NDPS metabolites enter target tissue using primary cultures of rat renal proximal tubular cells grown on permeable supports. C-Arylcuccinimide urotoxicity also is postulated to occur following conversion of the succinimide to reactive species (i.e. maleimides). Using the antiepiletic agent phensuximide (PSX) as our prototypic succinimide, in Aim 5 we will investigate (a) which PSX metabolites are urotoxicants (b) if PSX is biotransformed to a maleimide metabolite and (c) the ability of MESNA to attenuate PSX urotoxicity. Collectively, the results of these studies should add important, new knowledge about the nephrotoxic and urotoxic species of succinimides, cellular targets of the toxicant species and potential mechanisms of nephrotoxicity.
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