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

Marina Morigi, Simona Buelli, Cristina Zanchi, Lorena Longaretti, Daniela Macconi, Ariela Benigni, Daniela Moioli, Giuseppe Remuzzi, Carla Zoja

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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 κB (NF-κB) and activator protein-1 (Ap-1) to the extent that transfection with the dominant-negative mutant of IκB-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-κB-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-κB 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.

Original languageEnglish
Pages (from-to)1965-1975
Number of pages11
JournalAmerican Journal of Pathology
Issue number6
Publication statusPublished - Dec 2006

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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