Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2production
| Autor: | Nicolas G. Bazan, Jili Zhu, Richard J. Quigg, Xin J. Zhou, Moumita Chaki, Dongmei Lu, Bokkyoo Jun, Susan E. Zimmerman, Alysha Rauhauser, Chandra Mohan, Sarah Elhadi, Komal Vadnagara, Shan Shan Wang, Chongyu Ren, Binghua Li, Denise K. Marciano, Fatih Ozaltin, Matthew K. Topham, Massimo Attanasio, Hanquin Wang, Yong Du |
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| Přispěvatelé: | Çocuk Sağlığı ve Hastalıkları |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Hemolytic anemia Aging Diacylglycerol Kinase medicine.medical_specialty Thrombotic microangiopathy Endothelium Physiology Kidney Glomerulus Neovascularization Physiologic Renal function Biology Kidney Function Tests Dinoprostone Mice 03 medical and health sciences Glomerulonephritis Cell Movement Internal medicine medicine Animals Diacylglycerol kinase Microvascular occlusion Mice Knockout Wound Healing Macrophages Articles Urology & Nephrology medicine.disease Complement system Mice Inbred C57BL 030104 developmental biology Endocrinology medicine.anatomical_structure Cyclooxygenase 2 |
| Zdroj: | American Journal of Physiology-Renal Physiology. 310:F895-F908 |
| ISSN: | 1522-1466 1931-857X |
| DOI: | 10.1152/ajprenal.00431.2015 |
| Popis: | 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). DGKεis 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 E2are 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 E2supplementation 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. |
| Databáze: | OpenAIRE |
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