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Prostamide‐Mediated Protective Action of Anandamide on Nlrp3 Inflammasome Activation in Glomeruli of Mice with Hyperhomocysteinemia
Author(s) -
Xia Min,
Li Guangbi,
Conley Sabena M,
Meng Nan,
Boini Krishna M,
Ritter Joseph K,
Li PinLan
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.739.14
Subject(s) - inflammasome , podocyte , chemistry , endocrinology , medicine , in vivo , anandamide , pharmacology , kidney , inflammation , biology , proteinuria , antagonist , receptor , cannabinoid receptor , microbiology and biotechnology
Recent studies have shown anandamide (AEA), endogenous cannabinoids, and its major renal cyclooxygenase‐2 (Cox‐2) metabolite, prostamide E2 (PGE2‐EA), attenuate Hcys‐induced Nlrp3 inflammasome activation and injury in podocytes. The present study was designed to further test whether in vivo treatment of AEA suppresses Nlrp3 inflammasome activation and thereby prevents glomerular injury in mice with hHcys. Uninephrectomized C57BL/6J wild type mice were fed either normal chow (ND) or a folate free (FF) diet for 4 weeks to produce hHcys. By confocal microscopy we demonstrated that hHcys increased the colocalization of inflammasome proteins Nlrp3 with ASC or with caspase‐1 in glomeruli compared to them in ND fed mice. Correspondingly, IL‐1β production in these glomeruli of mice with hHcys was markedly increased. In vivo administration of AEA substantially inhibited Nlrp3 inflammasome formation and IL‐1β increases in glomeruli of hHcys mice. However, if these mice received Cox‐2 inhibitor, celecoxib, the inhibitory effect of AEA on Nlrp3 inflammasome activation was significantly reduced in glomeruli of mice with hHcys. Correspondingly, hHcys‐induced decrease in podocin and increase of desmin in glomeruli were also reversed by treatment of AEA. Proteinuria and glomerular sclerotic alterations as shown by increases in glomerular damage index (GDI) in mice with hHcys were also attenuated by AEA (GDI decreased from 1.5 in FF mice back to 0.5 in AEA treated hHcys mice). Although celecoxib itself had no effect on hHcys‐induced podocyte dysfunction and glomerular injury, it blocked the protective action of AEA. In Nlrp3 KO mice, hHcys failed to induce Nlrp3 inflammasome activation and glomerular injury and AEA also had no effect on glomerular inflammasomes and glomerular injury in these mice. From these results, we conclude that AEA protects glomeruli from hHcys‐induced Nlrp3 inflammasome activation and consequent glomerular injury through its metabolites such as prostamides via Cox‐2 pathway. Support or Funding Information Supported by NIH grants HL057244, HL075316, HL091464 and HL122937