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dc.contributor.authorZhu, Jili
dc.contributor.authorChaki, Moumita
dc.contributor.authorLu, Dongmei
dc.contributor.authorRen, Chongyu
dc.contributor.authorWang, Shan-Shan
dc.contributor.authorRauhauser, Alysha
dc.contributor.authorLi, Binghua
dc.contributor.authorZimmerman, Susan
dc.contributor.authorJun, Bokkyoo
dc.contributor.authorDu, Yong
dc.contributor.authorVadnagara, Komal
dc.contributor.authorWang, Hanquin
dc.contributor.authorElhadi, Sarah
dc.contributor.authorQuigg, Richard J.
dc.contributor.authorTopham, Matthew K.
dc.contributor.authorMohan, Chandra
dc.contributor.authorOzaltin, Fatih
dc.contributor.authorZhou, Xin J.
dc.contributor.authorMarciano, Denise K.
dc.contributor.authorBazan, Nicolas G.
dc.contributor.authorAttanasio, Massimo
dc.date.accessioned2019-12-10T10:39:59Z
dc.date.available2019-12-10T10:39:59Z
dc.date.issued2016
dc.identifier.issn1931-857X
dc.identifier.urihttps://doi.org/10.1152/ajprenal.00431.2015
dc.identifier.urihttp://hdl.handle.net/11655/14136
dc.description.abstractThrombotic 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-epsilon (DGKE) that encodes the lipid kinase DGK(epsilon) (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). DGKe 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 E-2 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 E-2 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.
dc.language.isoen
dc.publisherAmer Physiological Soc
dc.relation.isversionof10.1152/ajprenal.00431.2015
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectPhysiology
dc.subjectUrology & Nephrology
dc.titleLoss of Diacylglycerol Kinase Epsilon in Mice Causes Endothelial Distress and Impairs Glomerular Cox-2 and Pge(2) Production
dc.typeinfo:eu-repo/semantics/article
dc.typeinfo:eu-repo/semantics/publishedVersion
dc.relation.journalAmerican Journal Of Physiology-Renal Physiology
dc.contributor.departmentÇocuk Sağlığı ve Hastalıkları
dc.identifier.volume310
dc.identifier.issue9
dc.identifier.startpageF895
dc.identifier.endpageF908
dc.description.indexWoS


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