TY - JOUR
T1 - Loss of diacylglycerol kinase ε causes thrombotic microangiopathy by impairing endothelial VEGFA signaling
AU - Liu, Dingxiao
AU - Ding, Qiong
AU - Dai, Dao Fu
AU - Padhy, Biswajit
AU - Nayak, Manasa K.
AU - Li, Can
AU - Purvis, Madison
AU - Jin, Heng
AU - Shu, Chang
AU - Chauhan, Anil K.
AU - Huang, Chou Long
AU - Attanasio, Massimo
N1 - Funding Information:
The flow cytometry data were obtained at the Flow Cytometry Facility, which is a Carver College of Medicine/Holden Comprehensive Cancer Center core research facility at the University of Iowa. This facility is funded through user fees and the financial support of the Carver College of Medicine, Holden Comprehensive Cancer Center, and Iowa City Veterans Administration Medical Center. Research reported in this publication was supported by the National Center for Research Resources of the NIH under award number 1 S10 OD016199-01A1. The AKC lab is supported by grants from the NIH (R35HL139926, R01NS109910, U01NS113388) and by the Established Investigator Award 18EIA33900009 from the American Heart Association. We want to thank Harvey R. Herschman, for providing us the Cox2-COE mice.
Publisher Copyright:
© 2021, Liu et al.
PY - 2021/5/10
Y1 - 2021/5/10
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.146959
DO - 10.1172/jci.insight.146959
M3 - Article
C2 - 33986189
AN - SCOPUS:85105973743
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 9
M1 - e146959
ER -