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Gut Microbial Metabolite Trimethylamine‐N‐Oxide Instigates NLRP3 Inflammasomes Activation and Podocyte Injury
Author(s) -
Koka Saisudha,
Zhang Yang,
Li Ningjun,
Hussain Tahir,
Li PinLan,
Boini Krishna M
Publication year - 2017
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.31.1_supplement.1031.3
Subject(s) - podocyte , inflammasome , trimethylamine n oxide , podocin , chemistry , microbiology and biotechnology , transfection , kidney , medicine , biochemistry , biology , trimethylamine , receptor , proteinuria , gene
Gut microbe derived metabolite, Trimethylamine‐N‐oxide (TMAO) is elevated in chronic kidney disease (CKD) and contributes to the progression of renal disease and increases the risk of mortality in CKD. However, it remains unknown how TMAO induces chronic kidney diseases. The present study tested whether TMAO induces NLRP3 Inflammasomes formation and activation and thereby contributes to podocyte injury. Confocal microscopic analysis showed that TMAO treatment significantly increased the colocalization of NLRP3 with Asc or NLRP3 with caspase‐1 in podocytes compared to control cells. Pretreatment with Nlrp3 siRNA or Caspase‐1 inhibitor YVAD abolished the TMAO‐induced NLRP3 inflammasome formation. Correspondingly, TMAO treatment significantly increased the caspase‐1 activity (2.5 fold) and IL‐1β production (2.4 fold) compared to control cells. The Nlrp3 siRNA transfection significantly attenuated the TMAO‐induced caspase‐1 activity and IL‐1β production. Further RT‐PCR and confocal microscopic analysis showed that TMAO treatment significantly decreased the podocin expression (podocyte damage) compared to control cells. However, pretreatment with Nlrp3 siRNA or YVAD attenuated the TMAO‐induced podocin reduction. Furthermore, Nlrp3 siRNA transfection was found to preserve podocyte morphology by maintaining the distinct arrangement of F‐actin fibers normally lost in response to TMAO. It also prevented podocyte dysfunction by restoring TMAO‐induced suppression of VEGF production and secretion. Based on these results, it is concluded that TMAO‐induced the NLRP3 inflammasome formation and activation in podocytes and thereby by resulting in podocyte injury. Support or Funding Information DK104031