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Inhibition of Hyperhomocysteinemia‐Induced Inflammasome Activation and Glomerular Sclerosis by NLRP3 Gene Deletion
Author(s) -
Boini Krishna M.,
Xia Min,
Abais Justine M.,
Zhang Yang,
Gehr Todd W.,
Li PinLan
Publication year - 2013
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.27.1_supplement.704.6
Subject(s) - podocin , inflammasome , endocrinology , medicine , nephrin , knockout mouse , podocyte , chemistry , hyperhomocysteinemia , caspase 1 , inflammation , homocysteine , proteinuria , kidney , receptor
Hyperhomocysteinemia (hHcys) has been reported to initiate NLRP3 inflammasome formation and activation in podocytes, leading to glomerular dysfunction and sclerosis. However, it remains unknown whether Nlrp3 gene is critical for the activation of inflammasomes in glomeruli of hHcys mice. Uninephrectomized Nlrp3 knockout ( Nlrp3 − / − ) and wild type ( Nlrp3 +/+ ) mice were fed a folate free (FF) diet or normal chow (ND) for 4 weeks to produce hHcys. HPLC analysis revealed that plasma Hcys levels were significantly elevated in both Nalp3 − / − and Nalp3 +/+ mice fed a FF diet compared to ND fed mice. The FF diet significantly increased the colocalization of Nlrp3 with ASC or caspase‐1 in glomeruli of Nlrp3 +/+ , but not in Nlrp3 − / − mice, suggesting that hHcys‐enhanced the formation of Nlrp3 inflammasomes. Furthermore, colocalization of Nlrp3 with podocin indicates the enrichment of Nlrp3 in podocytes. In addition, biochemical analysis demonstrated that hHcys significantly increased the caspase‐1 activity and IL‐1β production in Nlrp3 +/+ mice, but not in Nlrp3 − / − mice. Correspondingly, the glomerular damage index (GDI) and urinary protein excretion were significantly higher in Nalp3 +/+ mice compared to ND fed mice. However, the hHcys‐induced increase in GDI and proteinuria were significantly lower in Nlrp3 − / − than in Nlrp3 +/+ mice (GDI in Nlrp3 +/+ : 2.9 ± 0.1 vs. Nlrp3 − / − : 1.3 ± 0.1). Immunocytochemical analysis showed that hHcys decreased expression of podocin and nephrin, but increased desmin, CD43 and F4/80 expression in glomeruli of Nlrp3 +/+ mice compared to Nlrp3 − / − mice. Based on these results, it is concluded that Nlrp3 is an essential component of Nlrp3 inflammasomes and that targeting Nlrp3 may be important therapeutic strategy to prevent inflammasome activation and thereby protect podocytes and glomeruli from hHcys‐induced injury (supported by NIH grants DK54927 and HL75316).