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

Am J Physiol Renal Physiol. 2008 May;294(5):F1185-94. doi: 10.1152/ajprenal.00442.2007. Epub 2008 Feb 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line
  • Endothelial Cells / metabolism*
  • Endothelin-1 / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Matrix / metabolism
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Guinea Pigs
  • Humans
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins
  • Kidney Glomerulus / cytology
  • Kidney Glomerulus / metabolism*
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / metabolism*
  • Podocytes / physiology*
  • Pre-Eclampsia / blood*
  • Pregnancy
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serum / chemistry


  • Endothelin-1
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NPHS2 protein
  • nephrin