98.5 - Exosome-Mediated Release of NLRP3 Inflammasome Products from Podocytes to Trigger Glomerular Inflammatory Response During Obesity

Guangbi Li (Virginia Commonwealth University), Dandan Huang (Virginia Commonwealth University), Yao Zou (Virginia Commonwealth University), Ningjun Li (Virginia Commonwealth University), Joseph Ritter (Virginia Commonwealth University), Pin-Lan Li (Virginia Commonwealth University)

The nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome products such as IL-1β, IL-18, and HMGB1 are critical factors to trigger glomerular inflammatory responses under different pathological conditions. The present study was designed to test a hypothesis that during obesity exosome release serves as the molecular mechanism mediating the release and action of NLRP3 inflammasome products from podocytes thereby leading to glomerular inflammation and sclerosis. By confocal microscopy and immunohistochemistry, NLRP3 inflammasome activation and associated T cell infiltration were found significantly enhanced in glomeruli of obese mice receiving high-fat diet (HFD). Nanoparticle tracking analysis showed that podocyte-derived exosomes containing NLRP3 inflammasome products remarkably increased in urine of these mice. By structured illumination microscopy, we observed the inhibition of lysosome-MVB interaction by visfatin, a pro-inflammatory adipokine, in podocytes isolated from mice on the normal diet, which was accompanied by enhanced exosome release. The HFD-induced NLRP3 inflammasome activation and exosome release in mouse glomeruli and visfatin-induced impairment of lysosome-MVB interaction in primary cultures of podocytes were attenuated by Smpd1 gene knockout but amplified by podocyte-specific Smpd1 gene overexpression (Smpd1 is the gene code of mouse acid sphingomyelinase). Correspondingly, HFD-induced podocyte injury, glomerulosclerosis, and proteinuria were enhanced in mice with podocyte-specific Smpd1 gene overexpression but reduced in Smpd1 gene knockout mice. Taken together, our results suggest that the release of exosomes containing NLRP3 inflammasome products from podocytes is critically implicated in the triggering of glomerular inflammatory response leading to glomerular sclerosis during obesity. The acid sphingomyelinase-ceramide signaling pathway plays a key role in this exosome-mediated release of NLRP3 inflammasome products.

Support or Funding Information

This study is supported by NIH grants DK054927 and DK120491.

This study isamp;nbsp;supported by NIH grants DK054927 and DK120491.