Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2 production

Jili Zhu, Moumita Chaki, Dongmei Lu, Chongyu Ren, Shan Shan Wang, Alysha Rauhauser, Binghua Li, Susan Zimmerman, Bokkyoo Jun, Yong Du, Komal Vadnagara, Hanquin Wang, Sarah Elhadi, Richard J. Quigg, Matthew K. Topham, Chandra Mohan, Fatih Ozaltin, Xin J. Zhou, Denise K. Marciano, Nicolas G. BazanMassimo Attanasio

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)F895-F908
JournalAmerican Journal of Physiology - Renal Physiology
Volume310
Issue number9
DOIs
StatePublished - May 1 2016

Fingerprint

Diacylglycerol Kinase
Thrombotic Microangiopathies
Dinoprostone
Cyclooxygenase 2
Endothelium
CD31 Antigens
Gene Components
Viverridae
Mutation
Complement Activation
Hemolytic Anemia
Cell Adhesion Molecules
Knockout Mice
Thrombocytopenia
Prostaglandins
Phosphotransferases
Phenotype
Kidney
Lipids
Membranes

Keywords

  • DGKE
  • Hemolytic uremic syndrome
  • Thrombotic microangiopathy

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2 production. / Zhu, Jili; Chaki, Moumita; Lu, Dongmei; Ren, Chongyu; Wang, Shan Shan; Rauhauser, Alysha; Li, Binghua; Zimmerman, Susan; Jun, Bokkyoo; Du, Yong; Vadnagara, Komal; Wang, Hanquin; Elhadi, Sarah; Quigg, Richard J.; Topham, Matthew K.; Mohan, Chandra; Ozaltin, Fatih; Zhou, Xin J.; Marciano, Denise K.; Bazan, Nicolas G.; Attanasio, Massimo.

In: American Journal of Physiology - Renal Physiology, Vol. 310, No. 9, 01.05.2016, p. F895-F908.

Research output: Contribution to journalArticle

Zhu, J, Chaki, M, Lu, D, Ren, C, Wang, SS, Rauhauser, A, Li, B, Zimmerman, S, Jun, B, Du, Y, Vadnagara, K, Wang, H, Elhadi, S, Quigg, RJ, Topham, MK, Mohan, C, Ozaltin, F, Zhou, XJ, Marciano, DK, Bazan, NG & Attanasio, M 2016, 'Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2 production', American Journal of Physiology - Renal Physiology, vol. 310, no. 9, pp. F895-F908. https://doi.org/10.1152/ajprenal.00431.2015
Zhu, Jili ; Chaki, Moumita ; Lu, Dongmei ; Ren, Chongyu ; Wang, Shan Shan ; Rauhauser, Alysha ; Li, Binghua ; Zimmerman, Susan ; Jun, Bokkyoo ; Du, Yong ; Vadnagara, Komal ; Wang, Hanquin ; Elhadi, Sarah ; Quigg, Richard J. ; Topham, Matthew K. ; Mohan, Chandra ; Ozaltin, Fatih ; Zhou, Xin J. ; Marciano, Denise K. ; Bazan, Nicolas G. ; Attanasio, Massimo. / Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2 production. In: American Journal of Physiology - Renal Physiology. 2016 ; Vol. 310, No. 9. pp. F895-F908.
@article{8980db771ea046008c662164d18b69c4,
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.",
keywords = "DGKE, Hemolytic uremic syndrome, Thrombotic microangiopathy",
author = "Jili Zhu and Moumita Chaki and Dongmei Lu and Chongyu Ren and Wang, {Shan Shan} and Alysha Rauhauser and Binghua Li and Susan Zimmerman and Bokkyoo Jun and Yong Du and Komal Vadnagara and Hanquin Wang and Sarah Elhadi and Quigg, {Richard J.} and Topham, {Matthew K.} and Chandra Mohan and Fatih Ozaltin and Zhou, {Xin J.} and Marciano, {Denise K.} and Bazan, {Nicolas G.} and Massimo Attanasio",
year = "2016",
month = "5",
day = "1",
doi = "10.1152/ajprenal.00431.2015",
language = "English (US)",
volume = "310",
pages = "F895--F908",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "9",

}

TY - JOUR

T1 - Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2 production

AU - Zhu, Jili

AU - Chaki, Moumita

AU - Lu, Dongmei

AU - Ren, Chongyu

AU - Wang, Shan Shan

AU - Rauhauser, Alysha

AU - Li, Binghua

AU - Zimmerman, Susan

AU - Jun, Bokkyoo

AU - Du, Yong

AU - Vadnagara, Komal

AU - Wang, Hanquin

AU - Elhadi, Sarah

AU - Quigg, Richard J.

AU - Topham, Matthew K.

AU - Mohan, Chandra

AU - Ozaltin, Fatih

AU - Zhou, Xin J.

AU - Marciano, Denise K.

AU - Bazan, Nicolas G.

AU - Attanasio, Massimo

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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.

AB - 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.

KW - DGKE

KW - Hemolytic uremic syndrome

KW - Thrombotic microangiopathy

UR - http://www.scopus.com/inward/record.url?scp=84984645053&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84984645053&partnerID=8YFLogxK

U2 - 10.1152/ajprenal.00431.2015

DO - 10.1152/ajprenal.00431.2015

M3 - Article

C2 - 26887830

AN - SCOPUS:84984645053

VL - 310

SP - F895-F908

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 9

ER -