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Protective effects of docosahexaenoic acid metabolites against homocysteine‐induced podocyte injury by inhibition of NLRP3 inflammasomes (1134.8)
Author(s) -
Abais Justine,
Xia Min,
Boini Krishna,
Li PinLan
Publication year - 2014
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.28.1_supplement.1134.8
Subject(s) - inflammasome , caspase 1 , docosahexaenoic acid , aim2 , podocyte , chemistry , nephrin , microbiology and biotechnology , colocalization , pyroptosis , biochemistry , biology , fatty acid , endocrinology , polyunsaturated fatty acid , kidney , receptor , proteinuria
Our recent studies have provided substantial evidence that elevated levels of homocysteine (Hcys) induce podocyte injury through activation of NLRP3 inflammasomes, importantly contributing to the initiation of the inflammatory response and eventual progression to glomerular sclerosis. Ω‐3 fatty acid docosahexaenoic acid (DHA) is widely investigated for its anti‐inflammatory properties, and DHA metabolite resolvin D1 (RvD1) is reported to aid in the resolution of inflammation. The present study tested whether RvD1 and the intermediate metabolite 17‐hydroxy docosahexaenoic acid (17‐HDHA) could prevent Hcys‐induced podocyte injury via inhibition of the NLRP3 inflammasome. By confocal microscopy, Hcys treatment was found to induce inflammasome formation in cultured podocytes, shown by an increase in colocalization between the 3 major inflammasome proteins, namely, NLRP3, apoptosis‐associated speck‐like protein (ASC), and caspase‐1. However, pretreatment of podocytes with either 17‐HDHA (100 nM) or RvD1 (60 nM) was able to inhibit this colocalization, indicating prevention of Hcys‐induced inflammasome formation. Hcys also increased caspase‐1 activation by 1.7‐fold and IL‐1β secretion by 2.2‐fold, two hallmarks of NLRP3 inflammasome activation, which was also significantly attenuated by both 17‐HDHA and RvD1. In addition to suppression of Hcys‐induced NLRP3 inflammasome formation and activation, 17‐HDHA and RvD1 treatment protected podocytes from Hcys‐induced injury and dysfunction. This was demonstrated in the restoration of VEGF secretion as well as the expression of podocyte specific marker podocin, both of which are impaired in Hcys‐treated podocytes. These results conclude that 17‐HDHA and RvD1 block Hcys‐induced podocyte damage through inhibition of the NLRP3 inflammasome, demonstrating a potential new mechanism for the protective effects of DHA‐derived metabolites 17‐HDHA and RvD1. Grant Funding Source : supported by NIH grants DK54927 and 1F31AG043289