Loss of DGKε induces endothelial cell activation and death independently of complement activation

Blood. 2015 Feb 5;125(6):1038-46. doi: 10.1182/blood-2014-06-579953. Epub 2014 Dec 10.


Atypical hemolytic uremic syndrome (aHUS) is classically described to result from a dysregulation of the complement alternative pathway, leading to glomerular endothelial cell (EC) damage and thrombosis. However, recent findings in families with aHUS of mutations in the DGKE gene, which is not an integral component of the complement cascade, led us to consider other pathophysiologic mechanisms for this disease. Here, we demonstrate that loss of DGKε expression/activity in EC induces an increase in ICAM-1 and tissue factor expression through the upregulation of p38-MAPK-mediated signals, thus highlighting a proinflammatory and prothrombotic phenotype of DGKε-deficient ECs. More interestingly, DGKE silencing also increases EC apoptosis and impairs EC migration and angiogenesis in vitro, suggesting that DGKE loss-of-function mutations impair EC repair and angiogenesis in vivo. Conversely, DGKE knockdown moderately decreases the expression of the complement inhibitory protein MCP on quiescent EC, but does not induce complement deposition on their surface in vitro. Collectively, our data strongly suggest that in DGKE-associated aHUS patients, thrombotic microangiopathy results from impaired EC proliferation and angiogenesis rather than complement-mediated EC lesions. Our study expands the current knowledge of aHUS mechanisms and has implications for the treatment of patients with isolated DGKE mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death
  • Cell Movement
  • Complement Activation*
  • Complement C3 / immunology
  • Diacylglycerol Kinase / genetics*
  • Diacylglycerol Kinase / immunology
  • E-Selectin / genetics
  • Endothelial Cells / cytology
  • Endothelial Cells / immunology*
  • Endothelial Cells / metabolism
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics
  • MAP Kinase Signaling System
  • Neovascularization, Physiologic
  • RNA Interference*
  • RNA, Small Interfering / genetics


  • Complement C3
  • E-Selectin
  • RNA, Small Interfering
  • Intercellular Adhesion Molecule-1
  • DGKE protein, human
  • Diacylglycerol Kinase