title: Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2 production.
abstract: Thrombotic microangiopathy (TMA) is a disorder characterized by microvascular occlusion that can lead to thrombocytopenia, hemolytic anemia, and glomerular damage. Complement activation is the central event in most cases of TMA. Primary forms of TMA are caused by mutations in genes encoding components of the complement or regulators of the complement cascade. Recently, we and others have described a genetic form of TMA caused by mutations in the gene diacylglycerol kinase-ε (DGKE) that encodes the lipid kinase DGKε (Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi MR, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji WZ, Overton JD, Mane SM, Nurnberg G, Altmuller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nurnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP. Nat Genet 45: 531-536, 2013; Ozaltin F, Li BH, Rauhauser A, An SW, Soylemezoglu O, Gonul II, Taskiran EZ, Ibsirlioglu T, Korkmaz E, Bilginer Y, Duzova A, Ozen S, Topaloglu R, Besbas N, Ashraf S, Du Y, Liang CY, Chen P, Lu DM, Vadnagara K, Arbuckle S, Lewis D, Wakeland B, Quigg RJ, Ransom RF, Wakeland EK, Topham MK, Bazan NG, Mohan C, Hildebrandt F, Bakkaloglu A, Huang CL, Attanasio M. J Am Soc Nephrol 24: 377-384, 2013). DGKε is unrelated to the complement pathway, which suggests that unidentified pathogenic mechanisms independent of complement dysregulation may result in TMA. Studying Dgke knockout mice may help to understand the pathogenesis of this disease, but no glomerular phenotype has been described in these animals so far. Here we report that Dgke null mice present subclinical microscopic anomalies of the glomerular endothelium and basal membrane that worsen with age and develop glomerular capillary occlusion when exposed to nephrotoxic serum. We found that induction of cyclooxygenase-2 and of the proangiogenic prostaglandin E2 are impaired in Dgke null kidneys and are associated with reduced expression of the antithrombotic cell adhesion molecule platelet endothelial cell adhesion molecule-1/CD31 in the glomerular endothelium. Notably, prostaglandin E2 supplementation was able to rescue motility defects of Dgke knockdown cells in vitro and to restore angiogenesis in a test in vivo. Our results unveil an unexpected role of Dgke in the induction of cyclooxygenase-2 and in the regulation of glomerular prostanoids synthesis under stress.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Nephrology, Renmin Hospital, Wuhan University, Hubei, Wuhan, China;
authors.forename: Jili
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Moumita
authors.initials: M
authors.lastname: Chaki
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Dongmei
authors.initials: D
authors.lastname: Lu
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Chongyu
authors.initials: C
authors.lastname: Ren
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Alysha
authors.initials: A
authors.lastname: Rauhauser
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Binghua
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Susan
authors.initials: S
authors.lastname: Zimmerman
authors.affiliation: Department of Neuroscience, Louisiana State University, New Orleans, Louisiana;
authors.forename: Bokkyoo
authors.initials: B
authors.lastname: Jun
authors.affiliation: Biomedical Engineering, University of Houston, Houston, Texas;
authors.forename: Yong
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Komal
authors.initials: K
authors.lastname: Vadnagara
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Institute of Basic Medical Sciences, Hubei University of Medicine, Hubei, Shiyan, China;
authors.forename: Hanquin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Sarah
authors.initials: S
authors.lastname: Elhadi
authors.affiliation: Department of Medicine, University of Buffalo, Buffalo, New York;
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Quigg
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah;
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Topham
authors.affiliation: Biomedical Engineering, University of Houston, Houston, Texas;
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
authors.affiliation: Department of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Ankara, Turkey; Nephrogenetics Laboratory, Department of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Ankara, Turkey;
authors.forename: Fatih
authors.initials: F
authors.lastname: Ozaltin
authors.affiliation: Renal Path Diagnostics, Pathologist BioMedical Laboratories and Department of Pathology, Baylor University Medical Center, Dallas, Texas; and.
authors.forename: Xin J
authors.initials: XJ
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Denise K
authors.initials: DK
authors.lastname: Marciano
authors.affiliation: Department of Neuroscience, Louisiana State University, New Orleans, Louisiana;
authors.forename: Nicolas G
authors.initials: NG
authors.lastname: Bazan
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Eugene McDermott Center for Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas massimo.attanasio@utsouthwestern.edu.
authors.forename: Massimo
authors.initials: M
authors.lastname: Attanasio
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D002465:Cell Movement; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D019852:Diacylglycerol Kinase / Q000235:genetics*; D015232:Dinoprostone / Q000096:biosynthesis*; D004727:Endothelium / Q000473:pathology*; D005921:Glomerulonephritis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D014945:Wound Healing
chemical_list: D051546:Cyclooxygenase 2; D019852:Diacylglycerol Kinase; D015232:Dinoprostone
keywords: DGKE; hemolytic uremic syndrome; thrombotic microangiopathy