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

J F Harriman1, X L Liu, M D Aleo

  • 1Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 638, Little Rock, Arkansas 72205-7199, USA.

Cell Death and Differentiation
|June 12, 2002
PubMed

Insights

Cellular ATP depletion triggers kidney cell death (oncosis) via endoplasmic reticulum (ER) calcium release and calpain activation. Protecting ER calcium stores prevents this toxicant-induced cell death.

Area of Science:

  • Cell Biology
  • Renal Physiology
  • Toxicology

Background:

  • Cell death, or oncosis, in renal proximal tubular cells is a significant concern in kidney injury.
  • Understanding the precise signaling pathways involved in oncosis is crucial for developing protective strategies.

Purpose of the Study:

  • To elucidate the roles of ATP content, endoplasmic reticulum (ER) Ca(2+) stores, cytosolic free Ca(2+) (Ca(2+)(f)), and calpain activity in rabbit renal proximal tubular (RPT) cell death signaling.
  • To investigate the sequence of events linking ATP depletion to RPT cell oncosis.

Main Methods:

  • Utilized antimycin A, a mitochondrial inhibitor, to induce ATP depletion in RPT cells.
  • Employed ER Ca(2+)-ATPase inhibitors (thapsigargin, cyclopiazonic acid) to manipulate ER Ca(2+) stores.
  • Measured cytosolic free Ca(2+) (Ca(2+)(f)) levels and calpain activity.
  • Assessed cell viability to determine the effects of interventions on oncosis.

Main Results:

  • Antimycin A induced rapid ATP depletion, correlating with a sustained increase in cytosolic free Ca(2+) (Ca(2+)(f)).
  • ER Ca(2+) release was identified as a key event preceding the increase in Ca(2+)(f) and subsequent calpain activation.
  • Pretreatment with ER Ca(2+)-ATPase inhibitors prevented antimycin A-induced Ca(2+)(f) increases and cell death, while post-treatment was ineffective.

Conclusions:

  • Extensive ATP depletion signals renal proximal tubular cell oncosis through a pathway involving ER Ca(2+) release, sustained cytosolic Ca(2+) increase, and calpain activation.
  • Depleting ER Ca(2+) stores before toxicant exposure effectively prevents the downstream signaling events leading to cell death.

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