Increased Expression of Circulating NLRP3 Inflammasome in Canines With Chronic Kidney Disease

Abstract

ObjectivesInflammation is a key component in the initiation and progression of chronic kidney disease (CKD) and can contribute to renal fibrosis and a gradual loss of renal function. Inflammasomes are multiprotein immune complexes and their activation contributes to inflammation. While inflammasome-related protein including NOD-like receptor family, pyrin domain-containing-3 (NLRP3) is important in acute and chronic kidney disorders in rodent models, the role of inflammasomes in renal disorders in canines is not clear. MethodsWe assessed gene expression levels of inflammatory markers, in the blood of dogs clinically diagnosed with CKD, post-mortem. Pathology reports indicated interstitial inflammation, fibrosis, and thickening of the Bowman’s capsule. RNA was extracted from blood collected at necropsy from dogs with CKD (n = 6; 11–15 yr) and controls (n = 6; 10–14 yr). Gene expression was investigated using the NanoString nCounter® platform, and results analyzed using the nSolver software. ResultsThere was a significant up-regulation in the level of NLRP3 in dogs with CKD when compared to controls (1.36 fold, P < 0.05). Consistent with this, there was also an increase in IL1b, one of the cytokines activated by the NLRP3 pathway, in CKD dogs (1.44 fold, ns). However, there was a decrease in IL18 (1.28 fold, ns), another cytokine activated downstream of NLRP3 pathway. Further, IL17 and IFNg, two cytokines activated by IL18, were barely undetectable in CKD dogs and in controls. These results indicate that the NLRP3-IL1b pathway may play a more important role in CKD in canines than the NLRP3-IL18 pathway. There was also an increase in the intercellular adhesion molecule-3 (ICAM3), a T-cell activator, in CKD dogs (1.76 fold, ns). In contrast, there was a significant decrease in IL7 and CD19 in CKD dogs (1.99 and 2.26 fold respectively, both P < 0.05 vs con). While IL7 is a growth factor for T and B-cells, it inhibits fibrosis-like response in renal epithelial cells in culture. Whether a decline in IL7 may also promote renal fibrosis in canines is not clear. Moreover, increased NLRP3 is also implicated in renal fibrosis. ConclusionsOur results indicate that the NLRP3 plays an important role in kidney disease. Nutritional interventions targeting the NLRP3-IL-1b pathway may be important in mitigating the inflammasome-mediated deleterious effects in CKD Funding SourcesHills PNC.