title: Depletion of endoplasmic reticulum calcium stores protects against hypoxia- and mitochondrial inhibitor-induced cellular injury and death.
abstract: We have shown previously that intracellular Ca+2 chelation and calpain inhibitors block the influx of extracellular Ca+2 and Cl- during the late phase of cell injury in renal proximal tubules (RPT) exposed to the mitochondrial inhibitor antimycin A. Since the endoplasmic reticulum (ER) is the major intracellular Ca+2 storage site, ER Ca+2 release/depletion may mediate the Ca+2 influx and cell death. Treatment of RPT suspensions with thapsigargin, an ER Ca+2-ATPase inhibitor, increased cytosolic free Caf+2 (Ca+2) levels from 122 +/- 7 to 322 +/- 55 nM within 10 sec of addition followed by a return to control levels within 3 min. A 5-min pretreatment of RPT suspensions with thapsigargin blocked antimycin A- and hypoxia-induced influx of extracellular Ca+2 and Cl- and the resulting cell death/lysis. These data suggest that ER Ca+2 release/depletion during cell injury may trigger a signaling cascade that causes extracellular Ca+2 influx followed by Cl- influx, cell swelling, and ultimately cell death/ lysis.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205-7199, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Waters
authors.forename: J K
authors.initials: JK
authors.lastname: Wong
authors.forename: R G
authors.initials: RG
authors.lastname: Schnellmann
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D002118:Calcium / Q000172:deficiency / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D002712:Chlorides / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D002712:Chlorides; D000968:Antimycin A; D019284:Thapsigargin; D007770:L-Lactate Dehydrogenase; D002118:Calcium