| Glutamate dehydrogenase requirement for apoptosis induced by aristolochic acid in renal tubular epithelial cells. | |
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MedLine Citation:
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PMID: 21901531 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Ingestion of aristolochic acids (AA) contained in herbal remedies results in a renal disease and, frequently, urothelial malignancy. The genotoxicity of AA in renal cells, including mutagenic DNA adduct formation, is well-documented. However, the mechanisms of AA-induced tubular atrophy and renal fibrosis are largely unknown. Epithelial cell death is a critical characteristic of these pathological conditions. To elucidate the mechanisms of AA-induced cytotoxicity, we explored AA-interacting proteins in tubular epithelial cells (TEC). We found that AA interacts with a mitochondrial enzyme glutamate dehydrogenase (GDH) and moderately inhibits its activity. We report that AA induces cell death in GDH-knockdown TEC preferentially via non-apoptotic means, whereas in GDH-positive cells, death was executed by both the non-apoptotic and apoptotic mechanisms. Apoptosis is an energy-reliant process and demands higher adenosine 5'-triphosphate (ATP) consumption than does the non-apoptotic cell death. We found that, after AAI treatment, the ATP depletion is more pronounced in GDH-knockdown cells. When we reduced ATP in TEC cells by inhibition of glycolysis and mitochondrial respiration, cell death mode switched from apoptosis and necrosis to necrosis only. In addition, in cells incubated at low glucose and no glutamine conditions, oxaloacetate and pyruvate reduced AAI-induced apoptosis our data suggest that AAI-GDH interactions in TEC are critical for the induction of apoptosis by direct inhibition of GDH activity. AA binding may also induce changes in GDH conformation and promote interactions with other molecules or impair signaling by GDH metabolic products, leading to apoptosis. |
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Authors:
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Victor Romanov; Terry Whyard; Radha Bonala; Francis Johnson; Arthur Grollman |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-7 |
Journal Detail:
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Title: Apoptosis : an international journal on programmed cell death Volume: - ISSN: 1573-675X ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-8 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9712129 Medline TA: Apoptosis Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, USA, Victor.Romanov@sbumed.org. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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