Document Detail

Proteinases in renal cell death.
MedLine Citation:
PMID:  8691504     Owner:  NLM     Status:  MEDLINE    
The role of proteinases in renal proximal tubule (RPT) cellular death was examined using specific inhibitors of proteinases. Rabbit RPT suspensions were incubated with antimycin A for 1 h or tetrafluoroethyl-L-cysteine (TFEC) for 4 h in the absence or presence of the specific cysteine proteinase inhibitor L-trans-epoxysuccinyl-leucylamido (4-guanidino)butane (E-64), the serine proteinase inhibitors N-p-tosyl-L-lysine chloromethyl ketone (TLCK) or 3,4-dichloroisocoumarin (DCS), the serine and cysteine proteinase inhibitors leupeptin or antipain, or the aspartic proteinase inhibitor pepstatin. E-64 and pepstatin decreased lactate dehydrogenase (LDH) release, a marker of cell death, from RPT exposed either to antimycin A or TFEC. TLCK, DCS, leupeptin, or antipain did not decrease antimycin A- or TFEC-induced cell death. Bromohydroquinone- or t-butylhydroperoxide-induced cell death was not decreased by any of the proteinase inhibitors. Loss of lysosomal membrane potential, indicated by neutral red release, occurred prior to the onset of antimycin A-induced cell death. Extensive inhibition of lysosomal cathepsins B and L by E-64 was correlated with cytoprotection. However, E-64 was only protective after some cell death had occurred. These results suggest that lysosomal cysteine and aspartic proteinases, but not serine proteinases, play a role in RPT cell death induced by antimycin A or TFEC. The observation that E-64 was only protective after some cell death had occurred suggests that lysosomal cathepsins are released from dying cells and subsequently attack the remaining viable cells.
X Yang; R G Schnellmann
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of toxicology and environmental health     Volume:  48     ISSN:  0098-4108     ISO Abbreviation:  J Toxicol Environ Health     Publication Date:  1996 Jul 
Date Detail:
Created Date:  1996-08-26     Completed Date:  1996-08-26     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7513622     Medline TA:  J Toxicol Environ Health     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  319-32     Citation Subset:  IM    
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, USA.
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MeSH Terms
Anti-Bacterial Agents / toxicity
Antimycin A / toxicity
Antipain / pharmacology
Carboxypeptidases / metabolism
Cathepsin A
Cathepsin B / metabolism
Cell Death / drug effects,  physiology
Coumarins / pharmacology
Cysteine / analogs & derivatives,  toxicity
Cysteine Proteinase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Endopeptidases / physiology*
Hydrocarbons, Fluorinated / toxicity
Hydroquinones / toxicity
Kidney Tubules, Proximal / cytology,  drug effects,  enzymology*
L-Lactate Dehydrogenase / metabolism
Leucine / analogs & derivatives,  pharmacology
Leupeptins / pharmacology
Lysosomes / drug effects,  metabolism
Membrane Potentials / drug effects
Pepstatins / pharmacology
Peroxides / toxicity
Reactive Oxygen Species / toxicity
Serine Proteinase Inhibitors / pharmacology*
Tosyllysine Chloromethyl Ketone / pharmacology
Grant Support
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Coumarins; 0/Cysteine Proteinase Inhibitors; 0/Hydrocarbons, Fluorinated; 0/Hydroquinones; 0/Leupeptins; 0/Pepstatins; 0/Peroxides; 0/Reactive Oxygen Species; 0/Serine Proteinase Inhibitors; 11076-29-2/Streptomyces pepsin inhibitor; 2104-86-1/Tosyllysine Chloromethyl Ketone; 24365-47-7/leupeptin; 37691-11-5/Antipain; 39324-30-6/pepstatin; 51050-59-0/3,4-dichloroisocoumarin; 52-90-4/Cysteine; 583-69-7/2-bromohydroquinone; 61-90-5/Leucine; 642-15-9/Antimycin A; 66701-25-5/E 64; 75-91-2/tert-Butylhydroperoxide; 94840-66-1/S-(1,1,2,2-tetrafluoroethyl)cysteine; EC Dehydrogenase; EC 3.4.-/Carboxypeptidases; EC 3.4.-/Endopeptidases; EC A; EC B

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