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Prevention of High Fat‐induced Podocyte Injury and Glomerular Sclerosis in Mice Lacking Nod‐like Receptor Protein 3: Role of Inflammasome Extinction

Recent studies have demonstrated that NLRP3 inflammasome formation and activation are an important early mechanism responsible for podocyte injury and glomerular inflammation in obese mice. However, it remains unknown whether Nlrp3 gene is critical for the activation of inflammasomes in glomeruli of obese mice. To answer this question, the Nlrp3 knockout (Nlrp3‐/‐) and wild type (Nlrp3+/+) mice were fed a high fat diet (HFD) or normal chow (ND) for 10 weeks to produce obesity. Confocal microscopic analysis showed that HFD increased the colocalization of NLRP3 with Asc or caspase‐1 in glomeruli of Nlrp3+/+, but not in Nlrp3‐/‐ mice, suggesting that obesity‐enhanced formation of Nlrp3 inflammasomes. Furthermore, colocalization of Nlrp3 with podocin indicates the enrichment of Nlrp3 in podocytes. In addition, biochemical analysis demonstrated that HFD significantly increased the caspase‐1 activity and IL‐1β production in Nlrp3+/+ mice, but not in Nlrp3‐/‐ mice. Correspondingly, the urinary protein and albumin excretion were significantly higher in Nalp3+/+ mice compared to ND fed mice. However, the HFD‐induced proteinuria were significantly lowered in Nlrp3‐/‐ compared to Nlrp3+/+ mice. In addition, Western blot analysis showed that HFD significantly increased the desmin, HMGB‐1 and RAGE expression in glomeruli of Nlrp3+/+ mice, but not in Nlrp3‐/‐ mice.Based on these results, it is concluded that Nlrp3 is an essential component of Nlrp3 inflammasomes and that extinction of Nlrp3 inflammasomes in podocytes protects podocytes and glomeruli from obesity‐induced injury (supported by NIH grant DK54927).