High Fat Diet Failed to Induce NALP3 Inflammasome Activation and Glomerular Injury in Apoptosis‐Associated Speck‐like Protein (ASC) Knockout Mice

Abstract

Inflammasome, an intracellular inflammatory machinery, plays a key role in the pathogenesis of obesity and associated disorders. The present study was performed to determine the role of key inflammasome adaptor molecule ASC in high fat diet (HFD)‐ induced inflammasome activation and glomerular injury. ASC gene knockout (Asc−/−) and wild type (Asc+/+) mice were fed a HFD or normal chow (ND) for 8 weeks to produce obesity and associated glomerular injury. HFD significantly increased the body weight, blood glucose levels and NADPH‐dependent superoxide (O2•−) production in Asc+/+mice compared to ND fed mice. However, such HFD‐induced body weight gain, blood glucose levels and O2•− production were attenuated in Asc−/− mice. Confocal microscopic analysis showed that the HFD enhanced the colocalization of NALP3 with ASC or Caspase‐1, the essential components of NALP3 inflammasomes, in glomeruli of Asc+/+ than in Asc−/− mice. Consistent with decreased inflammasome formation, the caspase‐1 activity and IL‐1β production were also significantly attenuated in Asc−/− mice fed a HFD. Morphological examinations showed that HFD induced more profound injury in glomeruli of Asc+/+ mice than Asc−/− mice(the glomerular damage index (GDI) in Asc+/+: 2.2 ± 0.1 vs. Asc−/−: 1.2 ± 0.1). This decreased GDI in Asc−/− mice on the HFD was accompanied by attenuated proteinuria and albuminuria. Fluorescent immunohistochemical examinations using podocin and desmin as a podocyte markers showed that the inflammasome formation induced by the HFD were mostly located in podocytes as demonstrated by co‐localization of podocin with NALP3 or desmin with NALP3. In conclusion, normal expression and function of ASC gene is critical to the formation and activation of NALP3 inflammasomes and associated glomerular injury in obesity (supported by NIH grants DK54927 and HL‐75316).