Proteases in renal cell death: calpains mediate cell death produced by diverse toxicants.
The role of proteases in renal cell death has received limited investigation. Calpains are non-lysosomal cysteine proteases that are Ca+2 activated. Calpain inhibitors that block the active site of calpains (calpain inhibitor 1 and 2) or the Ca+2 binding domain of calpains (PD150606) decreased calpain activity in rabbit renal proximal tubule (RPT) suspensions. The inhibition of calpain activity decreased cell death produced by the diverse toxicants antimycin A (mitochondrial inhibitor), tetrafluroethyl-L-cysteine (nephrotoxic halocarbon), bromohydroquinone (nephro-toxic quinone), t-butylhydroperoxide (model oxidant) and ionomycin (Ca+2 ionophore). In summary, calpains appear to play a common and critical role in cell injury produced by diverse toxicants with different mechanisms of action. The general cysteine protease inhibitor trans-epoxysuccinyl-L-leucylamido (4-guanidino)-butane (E-64) decreased antimycin A- and tetrafluoroethyl-L-cysteine-induced cell death but had no effect on bromohydroquinone- or t-butylhydroperoxide-induced cell death. Serine/cysteine protease inhibitors (antipain, leupeptin) were not cytoprotective to RPT exposed to any of the toxicants. The cytoprotection associated with E-64 correlated with inhibition of lysosomal cathepsins and E-64 was only cytoprotective after some cell death had occurred. Since some cell death occurred prior to the E-64 cytoprotective effect, lysosomal cathepsins may be released from dying cells and subsequently target the remaining viable cells.
Schnellmann
R G
RG
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205-7199, USA. schnellmannrickyg@exchange.uams.edu
Williams
S W
SW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D019610:Cytoprotection / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000201:enzymology*; D008247:Lysosomes / Q000378:metabolism; D011817:Rabbits
D004791:Enzyme Inhibitors; D002154:Calpain