Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE₂production

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.

Diacylglycerol Kinase alpha is Involved in the Vitamin E-Induced Amelioration of Diabetic Nephropathy in Mice

“…Recently, some groups reported that mutation in the DGKε gene caused kidney disiase 34, 35 . Moreover, it was also reported that the DGKε deficient mice showed multiple glomerular failures and that damage to morphology of normal podocyte 36 . Indeed, DGKε deficient mice have an increased severity of albuminuria by nephrotoxic serum which induces nephritis 36 .…”

Diacylglycerol Kinase-ε: Properties and Biological Roles

“…The original report showed that there were no major abnormalities with these animals (see Section Post-translational Modifications of DGKε Proteins; Rodriguez de Turco et al, 2001 ). The renal phenotype of this mouse model was recently re-evaluated in more detail: the animals developed mild signs of renal disease with age (Zhu et al, 2016 ). Interestingly, glomerular lesions were noted in Dgkε-null mice after exposure to doses of nephrotoxic serum that did not affect wild type littermates (Zhu et al, 2016 ).…”

“…The renal phenotype of this mouse model was recently re-evaluated in more detail: the animals developed mild signs of renal disease with age (Zhu et al, 2016 ). Interestingly, glomerular lesions were noted in Dgkε-null mice after exposure to doses of nephrotoxic serum that did not affect wild type littermates (Zhu et al, 2016 ). Mouse models of aHUS often require exposure to exogenous triggers to reveal their pathogenic potential (Pickering et al, 2006 ; Thurman et al, 2012 ; Vernon et al, 2016 ).…”

“…Data from the recent report focused on the Dgkε-null mice suggests that DGKε deficiency leads to systemic inability to induce cyclooxygenase-2 (Cox-2) (Zhu et al, 2016 ). This enzyme, which is responsible for inducible production of prostanglandins, was previously shown to be decreased in the brains of Dgkε-null mice after kindling (Lukiw et al, 2005 ).…”

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy

“…2 DGKE knockout mice have no apparent renal phenotype, but have subclinical abnormalities of the glomerular endothelium and basement membrane on EM, develop glomerular capillary occlusion when exposed to nephrotoxic serum, and have impaired production of cyclooxygenase 2 and prostaglandin E 2 . 13 Currently, DGKE nephropathy manifesting in aHUS has been reported in 35 individuals 1,14-19 and a nephrotic syndrome/MPGN-like phenotype in 9 individuals. 2 The collective characteristics were summarized recently by Azukaitis et al, 19 although without a detailed investigation of reported pathological diagnoses.…”