Endoplasmic reticulum Ca(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(2+) stores, cytosolic free Ca(2+) (Ca(2+)(f)) and calpain activity in the signaling of rabbit renal proximal tubular (RPT) cell death (oncosis). Increasing concentrations (0.3-10 microM) of the mitochondrial inhibitor antimycin A produced rapid ATP depletion that correlated to a rapid and sustained increase in Ca(2+)(f), but not phospholipase C activation. The ER Ca(2+)-ATPase inhibitors thapsigargin (5 microM) or cyclopiazonic acid (100 microM) alone produced similar but transient increases in Ca(2+)(f). Pretreatment with thapsigargin prevented antimycin A-induced increases in Ca(2+)(f) and antimycin A pretreatment prevented thapsigargin-induced increases in Ca(2+)(f). Calpain activity increased in conjunction with ER Ca(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(2+) release, a sustained increase in Ca(2+)(f) and calpain activation. Depletion of ER Ca(2+) stores prior to toxicant exposure prevents increases in Ca(2+)(f) and oncosis.
Harriman
J F
JF
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 638, Little Rock, Arkansas 72205-7199, USA.
Liu
X L
XL
Aleo
M D
MD
Machaca
K
K
Schnellmann
R G
RG
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002154:Calpain / Q000378:metabolism*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004963:Estrenes / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology; D011760:Pyrrolidinones / Q000494:pharmacology; D011817:Rabbits; D019284:Thapsigargin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D004963:Estrenes; D007211:Indoles; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D000968:Antimycin A; D019284:Thapsigargin; D000255:Adenosine Triphosphate; D010738:Type C Phospholipases; D002154:Calpain; D000252:Calcium-Transporting ATPases; D002118:Calcium; C000543:cyclopiazonic acid