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 (<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 (<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.

NOD1 downregulates intestinal serotonin transporter and interacts with other pattern recognition receptors

“…Our results showed that TLR2 activation leads to an increment in NOD1 expression (mRNA and protein) in Caco‐2/TC7 cells, and supporting this interdependence, NOD1 activation produced a decrement in TLR2 expression. Regarding TLR4, several authors have shown a synergic response with NOD1 (Huang et al, ), which agree with our data where TLR4 activation by LPS decreased significantly NOD1 expression in Caco‐2/TC7 cells. Furthermore, in the ileum of tlr4 −/− mice, NOD1 expression increased, which corroborates the fact that TLR4 activation could downregulate NOD1 mRNA and protein expression.…”

“…TLR4 is expressed, as TLR2, in the cell surface and recognizes LPS from Gram‐negative bacteria. NOD1, able to detect DAP present in all bacteria membrane, could also recognize LPS, resulting in a collaborative response with TLR4 (Huang et al, ). Moreover, TLR4 activation seems to inhibit ERK/MAPK downstream kinase, which is the intracellular pathway involved in NOD1's effect on SERT (Shinohara et al, ).…”

Short-Chain Fatty Acids Inhibit Oxidative Stress and Inflammation in Mesangial Cells Induced by High Glucose and Lipopolysaccharide

“…Oxidative stress and inflammation are inseparably linked as each causes and intensifies the other, which could cause glomerulosclerosis, tubular atrophy, and fibrosis [21]. Our previous research showed high glucose and LPS prime the NLRP3 inflammasome and NF-κB inflammatory signaling in GMCs via ROS/TXNIP pathway [22]. Up to present, several studies have looked into the effect of stress and inflammatory signaling pathways as effector mechanisms of SCFAs, the anti-inflammatory activity of SCFAs or GPR43 agonist were shown to inhibit the production of ROS and oxidative stress in this and other studies.…”

Network Pharmacology-based Prediction of Mechanism of Shenzhuo Formula for Application to DN

“…As shown in the GO enrichment analysis results, the potential targets of shenzhuo formula acting on DN were mainly associated with various biological processes, such as lipopolysaccharide-mediated signaling pathway, inflammatory response, positive regulation of cyclase activity, protein kinase B signaling, positive regulation of MAP kinase activity, response to estradiol, which have a strongly direct correlation with the pathogenesis of DN [28][29][30][31][32][33][34].…”