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Loss of Diacylglycerol Kinase ε Causes Thrombotic Microangiopathy by Impairing Endothelial Vascular Endothelial Growth Factor A Signaling: SA-OR29
Abstract   Peer reviewed

Loss of Diacylglycerol Kinase ε Causes Thrombotic Microangiopathy by Impairing Endothelial Vascular Endothelial Growth Factor A Signaling: SA-OR29

Dingxiao Liu, Qiong Ding, Madison Purvis, Biswajit Padhy, Chou-Long Huang and Massimo Attanasio
Journal of the American Society of Nephrology, Vol.31(10S), pp.38-39
10/2020
DOI: 10.1681/ASN.20203110S138d

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Abstract

Background: Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) accompanied by hemolytic anemia, thrombocytopenia, and acute renal failure due to glomerular damage. Mutations in complement genes have been identified in about 50% of aHUS cases. We reported that mutations in the gene DGKE, encoding the lipid kinase diacylglycerol kinase epsilon (DGKe) that is unrelated to the complement system, also cause aHUS. In the glomeruli, DGKE is expressed in endothelial cells and podocytes. The molecular mechanisms by which loss of DGKε causes TMA are not known. Phosphatidyl-inositol diphosphate [PtdIns(4,5)P2] levels are reduced in Dgke knockout cells. Since the disruption of vascular endothelial factor A (VEGFA) signaling in humans and mice results in glomerular lesions that resemble those in humans with loss-of-function mutations in DGKE, we hypothesized that loss of DGKE may impair VEGF signaling in endothelial cells due to shortage of PtdIns(4,5)P2. Methods: To test this hypothesis, we performed in vitro studies on DGKE knockdown human umbilical vein endothelial cells (HUVECs) and generated endothelial-specificTie2CreDgkef/f conditional knockout mice. Results: We found that signaling downstream of VEGFA receptor 2 (VEGFR2) is compromised in DGKE knockdown HUVECs due to decreased activation of Akt, a phenotype that is rescued by supplementation the culture medium with PtdIns(4,5)P2. Endothelial-specific Tie2CreDgkef/f conditional knockout mice spontaneously developed thrombocytopenia, schistocytosis, and renal insufficiency, indicating that the endothelium is the cellular compartment responsible of the DGKE disease. Remarkably, these mice also developed albuminuria at later times, indicating that the impairment of the glomerular barrier, which is characteristic of the DGKE disease, is a later and secondary event. Conclusions: Our data indicate that loss of DGKE compromises signaling downstream of VEGFR2 in endothelial cells by decreasing cellular levels of PtdIns(4,5)P2, inducing aHUS and, secondarily, disruption of the glomerular barrier. These results also implicate that pharmacological manipulation of the VEGFA signaling may be used to modify the clinical course of other forms of aHUS.

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