Shigatoxin-induced endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling

Am J Pathol. 2006 Dec;169(6):1965-75. doi: 10.2353/ajpath.2006.051331.


Shigatoxin (Stx) is the offending agent of post-diarrheal hemolytic uremic syndrome, characterized by glomerular ischemic changes preceding microvascular thrombosis. Because podocytes are highly sensitive to Stx cytotoxicity and represent a source of vasoactive molecules, we studied whether Stx-2 modulated the production of endothelin-1 (ET-1), taken as candidate mediator of podocyte dysfunction. Stx-2 enhanced ET-1 mRNA and protein expression via activation of nuclear factor kappaB (NF-kappaB) and activator protein-1 (Ap-1) to the extent that transfection with the dominant-negative mutant of IkappaB-kinase 2 or with Ap-1 decoy oligodeoxynucleotides reduced ET-1 mRNA levels. We propose a role for p38 and p42/44 mitogen-activated protein kinases (MAPKs) in mediating NF-kappaB-dependent gene transcription induced by Stx-2, based on data that Stx-2 phosphorylated p38 and p42/44 MAPKs and that MAPK inhibitors reduced transcription of NF-kappaB promoter/luciferase reporter gene construct induced by Stx-2. Stx-2 caused F-actin redistribution and intercellular gaps via production of ET-1 acting on ETA receptor, because cytoskeleton changes were prevented by ETA receptor blockade. Exogenous ET-1 induced cytoskeleton rearrangement and intercellular gaps via phosphatidylinositol-3 kinase and Rho-kinase pathway and increased protein permeability across the podocyte monolayer. These data suggest that the podocyte is a target of Stx, a novel stimulus for the synthesis of ET-1, which may control cytoskeleton remodeling and glomerular permeability in an autocrine fashion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • Animals
  • Antigens, Tumor-Associated, Carbohydrate / metabolism
  • Cell Differentiation
  • Cell Membrane Permeability
  • Cells, Cultured
  • Cytoskeleton / metabolism
  • Endothelin-1 / biosynthesis
  • Endothelin-1 / metabolism*
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / physiology
  • Podocytes / drug effects*
  • RNA, Messenger / metabolism*
  • Shiga Toxin 2 / pharmacology*
  • Signal Transduction
  • Transcription Factor AP-1 / physiology
  • Transcription, Genetic
  • Up-Regulation


  • Actins
  • Antigens, Tumor-Associated, Carbohydrate
  • Endothelin-1
  • Gb3 antigen
  • NF-kappa B
  • RNA, Messenger
  • Shiga Toxin 2
  • Transcription Factor AP-1
  • Mitogen-Activated Protein Kinases