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(American Journal of Pathology. 2006;169:1965-1975.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051331

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*{dagger} and Carla Zoja*

From the Mario Negri Institute for Pharmacological Research,* and the Unit of Nephrology and Dialysis,{dagger} Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy

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 {kappa}B (NF-{kappa}B) and activator protein-1 (Ap-1) to the extent that transfection with the dominant-negative mutant of I{kappa}B-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-{kappa}B-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-{kappa}B 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.




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