High Glucose and Lipopolysaccharide Activate NOD1- RICK-NF-κB Inflammatory Signaling in Mesangial Cells

Abstract

Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus (DM) and diabetic nephropathy (DN). The TLR2, TLR4, and NLRP3 inflammasomes of the innate immune system produce various proinflammatory cytokines and are critically involved in inflammatory responses in kidney tissues. The NOD-like receptor (NLR) NOD1 is involved in the NF-κB inflammatory signaling pathway and has an important role in the development of insulin resistance. Extracellular stimuli such as high glucose or lipopolysaccharide (LPS) can induce NOD1-RICK to activate NF-κB, which is associated with diabetes and other chronic inflammatory conditions. It is currently unknown whether NOD1-RICK-mediated NF-κB signaling is involved in DN pathogenesis. In this study, expression of NOD1, RICK, IκBα, NF-κB and IL-1β was detected in cultured rat glomerular mesangial cells (rGMCs) stimulated with high concentrations of glucose and LPS. ML130, a NOD1 inhibitor, was used to investigate the role of the NOD1 signaling pathway in DN inflammation. Our results showed that high glucose or LPS increased the protein and mRNA expression of NOD1, RICK,NF-κBp65 and IL-1β, but attenuated IκBα expression (P<0.05). These changes were synergistically enhanced by stimulating with high glucose and LPS. However, pretreatment with the NOD1 inhibitor ML130 significantly reversed these changes (P<0.05). These combined results support the hypothesis that high glucose and LPS can activate the NOD1-RICK-NF-κB inflammatory signaling pathway via the NOD1 receptor, and may participate in the development of DN.

Key words

high glucose - lipopolysaccharide - NOD1/NF-κB - diabetic nephropathy

• References

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