Endoplasmic reticulum Ca super(2+) signaling and calpains mediate renal cell death

The goal of the current study was to determine the roles of ATP content, endoplasmic reticulum (ER) Ca super(2+) stores, cytosolic free Ca super(2+) (Ca super(2) sub(f) super(+)) and calpain activity in the signaling of rabbit renal proximal tubular (RPT) cell death (oncosis). Increasing concentrati...

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Veröffentlicht in:Cell death and differentiation 2002-07, Vol.9 (7), p.734-741
Hauptverfasser: Harriman, J F, Liu, X L, Aleo, MD, Machaca, K, Schnellmann, R G
Format: Artikel
Sprache:eng
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Zusammenfassung:The goal of the current study was to determine the roles of ATP content, endoplasmic reticulum (ER) Ca super(2+) stores, cytosolic free Ca super(2+) (Ca super(2) sub(f) super(+)) and calpain activity in the signaling of rabbit renal proximal tubular (RPT) cell death (oncosis). Increasing concentrations (0.3-10 mu M) of the mitochondrial inhibitor antimycin A produced rapid ATP depletion that correlated to a rapid and sustained increase in Ca super(2) sub(f) super(+), but not phospholipase C activation. The ER Ca super(2+)-ATPase inhibitors thapsigargin (5 mu M) or cyclopiazonic acid (100 mu M) alone produced similar but transient increases in Ca super(2) sub(f) super(+). Pretreatment with thapsigargin prevented antimycin A-induced increases in Ca super(2) sub(f) super(+) and antimycin A pretreatment prevented thapsigargin-induced increases in Ca super(2) sub(f) super(+). Calpain activity increased in conjunction with ER Ca super(2+) release. Pretreatment, but not post-treatment, with thapsigargin or cyclopiazonic acid prevented antimycin A-induced cell death. These data demonstrate that extensive ATP depletion signals oncosis through ER Ca super(2+) release, a sustained increase in Ca super(2) sub(f) super(+) and calpain activation. Depletion of ER Ca super(2+) stores prior to toxicant exposure prevents increases in Ca super(2) sub(f) super(+) and oncosis.
ISSN:1350-9047
DOI:10.1038/sj.cdd.4401029