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Mitochondrial protein phosphatase 2A regulates cell death induced by simulated ischemia in kidney NRK-52E cells

Chun Chui Tsao1, Alina Felicia Nica, Svitlana M Kurinna

  • 1Division of Cell Signaling, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center, Houston, Texas, USA.

Cell Cycle (Georgetown, Tex.)
|August 19, 2007
PubMed

Insights

Acute kidney injury involves cell death pathways. Protein phosphatase 2A (PP2A) activation, specifically involving the B56 alpha subunit, is crucial for this cell death during simulated renal ischemia.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Signaling

Background:

  • Acute kidney injury (AKI) following ischemic events leads to high mortality.
  • The specific stress-signaling pathways activated during renal ischemia remain largely unknown.
  • Protein phosphatase 2A (PP2A) is recognized as a key regulator of cellular death processes.

Purpose of the Study:

  • To investigate the role of PP2A in ischemia-induced cell death within kidney epithelial cells.
  • To elucidate the involvement of specific PP2A regulatory subunits in renal ischemia.
  • To understand the signaling mechanisms linking simulated ischemia to PP2A activation and cell death.

Main Methods:

  • Utilized an in vitro model of simulated renal ischemia using rat renal tubule epithelial NRK-52E cells.
  • Assessed cell death mechanisms, including necrosis and apoptosis.
  • Measured PP2A activity, expression of PP2A regulatory subunits (B56 alpha), and protein kinase C alpha (PKC alpha) levels.
  • Investigated the effects of ceramide treatment and PP2A inhibition on cell survival.
  • Examined the impact of overexpressing specific PP2A subunits (B56 alpha, B55) on ischemia-induced cell death.

Main Results:

  • Simulated ischemia induced both necrosis and apoptosis in NRK-52E cells.
  • Ischemia activated PP2A and upregulated the PP2A B56 alpha regulatory subunit.
  • PKC alpha was suppressed, while B56 alpha was upregulated, consistent with PP2A activation.
  • Ceramide mimicked ischemia by suppressing PKC alpha and activating PP2A.
  • Inhibition of PP2A conferred protection against cell death.
  • Overexpression of B56 alpha, but not B55, exacerbated ischemia-induced cell death.

Conclusions:

  • Activation of a PP2A isoform containing the B56 alpha regulatory subunit is essential for ischemia-induced cell death in proximal tubule kidney epithelial cells.
  • PP2A signaling, modulated by PKC alpha and potentially ceramide, plays a critical role in the cellular response to renal ischemia.
  • Targeting PP2A activity or its B56 alpha subunit may offer therapeutic strategies for AKI.

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