Document Detail


Cytoprotective effects of adenosine and inosine in an in vitro model of acute tubular necrosis.
MedLine Citation:
PMID:  19906119     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: We have established an in vitro model of acute tubular necrosis in rat kidney tubular cells, using combined oxygen-glucose deprivation (COGD) and screened a library of 1280 pharmacologically active compounds for cytoprotective effects.
EXPERIMENTAL APPROACH: We used in vitro cell-based, high throughput, screening, with cells subjected to COGD using hypoxia chambers, followed by re-oxygenation. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and the Alamar Blue assay measured mitochondrial respiration and the lactate dehydrogenase assay was used to indicate cell death. ATP levels were measured using a luminometric assay.
KEY RESULTS: Adenosine markedly reduced cellular injury, with maximal cytoprotective effect at 100 microM and an EC(50) value of 14 microM. Inosine was also found to be cytoprotective. The selective A(3) adenosine receptor antagonist MRS 1523 attenuated the protective effects of adenosine and inosine, while an A(3) adenosine receptor agonist provided a partial protective effect. Adenosine deaminase inhibition attenuated the cytoprotective effect of adenosine but not of inosine during COGD. Inhibition of adenosine kinase reduced the protective effects of both adenosine and inosine during COGD. Pretreatment of the cells with adenosine or inosine markedly protected against the fall in cellular ATP content in the cells subjected to COGD.
CONCLUSIONS AND IMPLICATIONS: The cytoprotection elicited by adenosine and inosine in a model of renal ischaemia involved both interactions with cell surface adenosine receptors on renal tubular epithelial cells and intracellular metabolism and conversion of adenosine to ATP.
Authors:
Katalin Módis; Domokos Gero; Nóra Nagy; Petra Szoleczky; Zoltán Dóri Tóth; Csaba Szabó
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  158     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-11-12     Completed Date:  2010-02-25     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1565-78     Citation Subset:  IM    
Affiliation:
CellScreen Applied Research Center, Semmelweis University Medical School, Budapest, Hungary.
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MeSH Terms
Descriptor/Qualifier:
Adenosine / administration & dosage,  metabolism,  pharmacology*
Adenosine Triphosphate / metabolism
Animals
Cell Death / drug effects
Cell Hypoxia
Cytoprotection / drug effects*
Epithelial Cells / drug effects,  metabolism
Glucose / metabolism
Inosine / pharmacology*
Kidney Tubular Necrosis, Acute / drug therapy*,  physiopathology
Kidney Tubules / cytology,  drug effects,  pathology
L-Lactate Dehydrogenase / metabolism
Mitochondria / drug effects,  metabolism
Oxygen / metabolism
Rats
Receptors, Purinergic P1 / drug effects,  metabolism
Grant Support
ID/Acronym/Agency:
R01 GM66189/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Receptors, Purinergic P1; 50-99-7/Glucose; 56-65-5/Adenosine Triphosphate; 58-61-7/Adenosine; 58-63-9/Inosine; 7782-44-7/Oxygen; EC 1.1.1.27/L-Lactate Dehydrogenase
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