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Loss of diacylglycerol kinase ε causes thrombotic microangiopathy by impairing endothelial VEGFA signaling
Dingxiao Liu, … , Chou-Long Huang, Massimo Attanasio
Dingxiao Liu, … , Chou-Long Huang, Massimo Attanasio
Published May 10, 2021
Citation Information: JCI Insight. 2021;6(9):e146959. https://doi.org/10.1172/jci.insight.146959.
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Research Article Nephrology

Loss of diacylglycerol kinase ε causes thrombotic microangiopathy by impairing endothelial VEGFA signaling

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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.

Authors

Dingxiao Liu, Qiong Ding, Dao-Fu Dai, Biswajit Padhy, Manasa K. Nayak, Can Li, Madison Purvis, Heng Jin, Chang Shu, Anil K. Chauhan, Chou-Long Huang, Massimo Attanasio

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Figure 5

A stable PGE2-analog rescues the phenotype of Tie2CreDgkefl/fl mice.

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A stable PGE2-analog rescues the phenotype of Tie2CreDgkefl/fl mice.
(A)...
(A) Representative bright-field microscopy images of glomeruli of PAS-stained Tie2CreDgkefl/fl mouse kidneys and (B) Tie2CreDgkefl/fl mouse kidneys after 4 weeks of subcutaneous infusion of the PGE2 stable analog dmPGE2. The occlusion of the glomerular capillaries is rescued after the dmPGE2 treatment. Scale bars are 50 μm. (C) Smears of blood from Tie2CreDgkefl/fl knockout mice and (D) Tie2CreDgkefl/fl mice after dmPGE2 treatment at 3 months of age. Tie2CreDgkefl/fl knockout mice show numerous schistocytes (arrows) and circulating reticulocytes (arrowheads). Scale bars are 50 μm. (E–H) Serum hemoglobin, circulating PLT, BUN, and urine ACR in Tie2CreDgkefl/fl compared with dmPGE2-treated Tie2CreDgkefl/fl mice at 8, 10, and 12 weeks of age. Data are presented as mean ± SD. *: P < 0.05, **: P < 0.01 by Student’s t test. n = 6 mice per group.

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ISSN 2379-3708

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