Abstract
Ceramide has been reported to initiate inflammasome formation and activation in obesity and different pathological conditions. The present study was performed to explore the role of acid sphingomyelinase (Asm) in the development of high fat diet (HFD)‐induced inflammasome formation and activation and consequent glomerular injury. Asm knockout (Asm−/−) and wild type (Asm+/+) mice were fed a HFD or normal chow for 6 weeks to produce obesity and associated glomerular injury. HFD significantly increased the body weight, renal Asm activity, O2.− production, and ceramide production in Asm+/+mice than in control diet‐fed mice. However, such HFD‐induced increases in body weight, Asm activity, O2− production and ceramide production was attenuated in asm−/− mice. Confocal fluorescent microscopy showed that HFD enhanced the colocalization of NALP3 with ASC or Caspase‐1, the essential components of NALP3 inflammasomes, in glomeruli of Asm+/+ than in Asm−/− mice. In consistency with decreased inflammasome formation, the caspase‐1 activity and IL‐1β production was significantly attenuated in Asm−/− mice fed a HFD. Morphological examinations showed that HFD induced profound injury in glomeruli of Asm+/+ mice which was markedly attenuated in Asm−/− mice(the glomerular damage index (GDI) in Asm+/+: 2.1 ± 0.05 vs. Asm−/−: 1.05 ± 0.04). The decreased GDI in Asm−/− mice was accompanied by attenuated proteinuria and albuminuria. Fluorescent immunohistochemical examinations using podocin as a podocyte marker showed that the inflammasome formation induced by the HFD were mostly located in podocytes as demonstrated by co‐localization of podocin with NALP3 or Caspase‐1. In conclusion, these observations disclose a pivotal role of Asm in the HFD‐induced inflammasome formation and consequent glomerular inflammation and injury (supported by NIH grants DK54927, HL‐091464 and HL‐75316).
Published Version
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