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

Abstract：

: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.

journal_name

Blood

journal_title

Blood

authors

Bruneau S,Néel M,Roumenina LT,Frimat M,Laurent L,Frémeaux-Bacchi V,Fakhouri F

doi

10.1182/blood-2014-06-579953

subject

Has Abstract

pub_date

2015-02-05 00:00:00

pages

1038-46

issue

6

eissn

0006-4971

issn

1528-0020

pii

blood-2014-06-579953

journal_volume

125

pub_type

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