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Cytoprotective signaling by activated protein C requires protease-activated receptor-3 in podocytes

Thati Madhusudhan1, Hongjie Wang, Beate K Straub

  • 1Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Germany.

Blood
|November 26, 2011
PubMed

Insights

Activated protein C (aPC) protects kidney podocytes via a novel signaling pathway involving protease-activated receptor-3 (PAR-3) and PAR-2/PAR-1. This mechanism inhibits apoptosis and reduces kidney injury.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Activated protein C (aPC) exhibits cytoprotective effects, but its signaling mechanisms in kidney podocytes are undefined.
  • Existing knowledge indicates aPC protects glomerular endothelial cells via PAR-1 and EPCR, but podocyte-specific pathways remain elusive.

Purpose of the Study:

  • To elucidate the signaling mechanism by which aPC confers cytoprotection to podocytes.
  • To identify the specific receptors and pathways involved in aPC-mediated podocyte protection.

Main Methods:

  • Investigated aPC signaling in podocytes using biochemical assays and genetic manipulation.
  • Examined aPC-induced activation of protease-activated receptors (PARs) and their downstream effects.
  • Assessed the role of PAR-3, PAR-2, PAR-1, and caveolin-1 in aPC-mediated cytoprotection.
  • Evaluated the in vivo effects of aPC in a mouse model of podocyte injury.

Main Results:

  • Identified a novel aPC/PAR-dependent cytoprotective signaling mechanism in podocytes.
  • aPC inhibits podocyte apoptosis via proteolytic activation of PAR-3, independent of EPCR.
  • PAR-3 requires aPC-induced heterodimerization with PAR-2 (human) or PAR-1 (mouse) to signal.
  • This pathway involves caveolin-1 dephosphorylation and confers protection against LPS-induced podocyte injury and proteinuria in vivo.
  • Genetic deletion of PAR-3 abrogated the nephroprotective effects of aPC.

Conclusions:

  • Discovered a novel, cell-specific signaling mechanism for aPC in kidney podocytes involving PAR-3 and PAR-2/PAR-1 heterodimerization.
  • This pathway highlights the plasticity of aPC signaling and its dependence on specific receptor interactions.
  • Findings suggest potential for developing targeted therapies for kidney diseases based on these specific signaling complexes.

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