Abstract
Loss of function of the lipid kinase diacylglycerol kinase ε (DGKε), encoded by the gene DGKE, causes a form of atypical hemolytic uremic syndrome that is not related to abnormalities of the alternative pathway of the complement, by mechanisms that are not understood. By generating a potentially novel endothelial specific Dgke-knockout mouse, we demonstrate that loss of Dgke in the endothelium results in impaired signaling downstream of VEGFR2 due to cellular shortage of phosphatidylinositol 4,5-biphosphate. Mechanistically, we found that, in the absence of DGKε in the endothelium, Akt fails to be activated upon VEGFR2 stimulation, resulting in defective induction of the enzyme cyclooxygenase 2 and production of prostaglandin E2 (PGE2). Treating the endothelial specific Dgke-knockout mice with a stable PGE2 analog was sufficient to reverse the clinical manifestations of thrombotic microangiopathy and proteinuria, possibly by suppressing the expression of matrix metalloproteinase 2 through PGE2-dependent upregulation of the chemokine receptor CXCR4. Our study reveals a complex array of autocrine signaling events downstream of VEGFR2 that are mediated by PGE2, that control endothelial activation and thrombogenic state, and that result in abnormalities of the glomerular filtration barrier.
Keywords:
Inositol phosphates; Microcirculation; Nephrology.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Atypical Hemolytic Uremic Syndrome / genetics*
-
Atypical Hemolytic Uremic Syndrome / metabolism
-
Autocrine Communication
-
Cyclooxygenase 2 / metabolism
-
Diacylglycerol Kinase / genetics*
-
Diacylglycerol Kinase / metabolism
-
Dinoprostone / metabolism
-
Dinoprostone / pharmacology
-
Endothelium, Vascular / drug effects
-
Endothelium, Vascular / metabolism*
-
Endothelium, Vascular / physiopathology
-
Gene Knockdown Techniques
-
Glomerular Filtration Barrier / drug effects
-
Glomerular Filtration Barrier / metabolism
-
Human Umbilical Vein Endothelial Cells
-
Humans
-
Matrix Metalloproteinase 2 / metabolism
-
Mice
-
Mice, Knockout
-
Phosphatidylinositol 4,5-Diphosphate / metabolism
-
Proto-Oncogene Proteins c-akt / metabolism*
-
Receptors, CXCR4 / metabolism
-
Thrombotic Microangiopathies / genetics
-
Thrombotic Microangiopathies / metabolism
-
Vascular Endothelial Growth Factor A / metabolism*
-
Vascular Endothelial Growth Factor A / pharmacology
-
Vascular Endothelial Growth Factor Receptor-2 / metabolism*
Substances
-
Phosphatidylinositol 4,5-Diphosphate
-
Receptors, CXCR4
-
Vascular Endothelial Growth Factor A
-
Cyclooxygenase 2
-
DGKE protein, human
-
Dgke protein, mouse
-
Diacylglycerol Kinase
-
Vascular Endothelial Growth Factor Receptor-2
-
Proto-Oncogene Proteins c-akt
-
Matrix Metalloproteinase 2
-
Dinoprostone