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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/F1185    most recent 00442.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Collino, F. Articles by Camussi, G. Search for Related Content PubMed PubMed Citation Articles by Collino, F. Articles by Camussi, G.

Preeclamptic sera induce nephrin shedding from podocytes through endothelin-1 release by endothelial glomerular cells

¹Department of Internal Medicine, Research Centre for Experimental Medicine and Molecular Biotechnology Center, and ²Department of Gynaecology and Obstetrics, University of Torino, Torino, Italy

Submitted 21 September 2007 ; accepted in final form 15 February 2008

In preeclampsia (PE), proteinuria has been associated with a reduced expression of nephrin by podocytes. In the present study, we investigated in vitro on human cultured podocytes the mechanism responsible for nephrin loss in PE. Sera from patients with PE did not directly downregulate the expression of nephrin. In contrast, conditioned medium obtained from glomerular endothelial cells incubated with PE sera induced loss of nephrin and synaptopodin, but not of podocin, from podocytes. Nephrin loss was related to a rapid shedding of the protein from the cell surface due to cleavage of its extracellular domain by proteases and to cytoskeleton redistribution. The absence of nephrin mRNA downregulation together with nephrin reexpression within 24 h confirm that the loss of nephrin was not related to a reduced synthesis. Studies with an endothelin-1 (ET-1) receptor antagonist that abrogated the loss of nephrin triggered by glomerular endothelial conditioned medium of PE sera indicated that ET-1 was the main effector of nephrin loss. Indeed, ET-1 was synthesized and released from glomerular endothelial cells when incubated with PE sera, and recombinant ET-1 triggered nephrin shedding from podocytes. Moreover, VEGF blockade induced ET-1 release from endothelial cells, and in turn the conditioned medium obtained triggered nephrin loss. In conclusion, the present study identifies a potential mechanism of nephrin loss in PE that may link endothelial injury with enhanced glomerular permeability.

slit diaphragm; synaptopodin; proteinuria; VEGF blockade

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