Abstract Body: Atherosclerosis is highly prevalent in patients with chronic kidney disease (CKD). Cardiovascular mortality is 10 to 20 times higher in CKD patients than the general population. One clinical study also revealed an independent, graded association between lower levels of the estimated glomerular filtration rate (eGFR) and the risks of death, cardiovascular events, and hospitalization. However, the underlying pathogenesis of CKD-driven cardiovascular disease progression is still less understood. In the present study, we hypothesized that circulating uremic toxin in CKD would increase systemic and target organ inflammation, which would result in atherosclerosis progression.
12-week-old male Ldlr KO mice underwent 5/6 nephrectomy to induce CKD (n = 14) or no surgery (n = 8) and then were fed on western diet for 12 weeks. Serum levels of urea in CKD mice significantly increased compared to control mice (19±1.4 vs. 46±4.9; p<0.0001). GFR also significantly decreased in CKD mice, further confirming kidney dysfunction. Serum levels of the NLRP3-dependent cytokine IL-18 markedly increased in CKD mice (2306±1144 vs. 1398±263; p<0.05). Moreover, NETosis, an NLRP3 dependent proinflammatory process in neutrophils, and inflammatory cell infiltration remarkably increased in CKD mouse heart and kidney compared to control mice. These results suggest that NLRP3 inflammasome may be activated by uremic toxin, leading to elevations of the NLRP3 downstream biomarkers, circulating IL-18 and NETosis, in cardiovascular tissues. More importantly, CKD mice showed aortic plaque area increase by 35% (P < 0.05) and greater vessel lesions in branch arteries of aorta. Serum levels of cholesterol and triglyceride were similar between CKD mice and control mice (765±42 vs. 758±16 and 544±158 vs. 523±151; both p>0.05), indicating that plaque size is independent of serum cholesterol levels.
In conclusion, the present findings suggest that uremia promotes not only systemic inflammation, but also inflammatory changes in remote organs, which leads to atherosclerotic plaque expansion mediated by activating NLRP3 inflammasome. Therefore, inhibition of NLRP3 inflammasome activation could be a novel treatment for patients with CKD to reduce cardiovascular risk.