Abstract
Background The arteriovenous fistula ( AVF ) is the preferred hemodialysis access for patients with chronic kidney disease. Chronic kidney disease can increase neointima formation, which greatly contributes to AVF failure by an unknown mechanism. Our study aimed to determine the role of nucleotide-binding oligomerization domain-like receptor protein 3 ( NLRP 3) in neointima formation induced by experimental AVF s in the presence of chronic kidney disease. Methods and Results From our findings, NLRP 3 was upregulated in the intimal lesions of AVF s in both uremic mice and patients. Smooth muscle-specific knockout NLRP 3 mice exhibited markedly decreased neointima formation in the outflow vein of AVF s. Compared with primary vascular smooth muscle cells isolated from control mice, those isolated from smooth muscle-specific knockout NLRP 3 mice showed compromised proliferation, migration, phenotypic switching, and a weakened ability to activate mononuclear macrophages. To identify how NLRP 3 functions, several small-molecule inhibitors were used. The results showed that NLRP 3 regulates smooth muscle cell proliferation and migration through Smad2/3 phosphorylation rather than through caspase-1/interleukin-1 signaling. Unexpectedly, the selective NLRP 3-inflammasome inhibitor MCC 950 also repressed Smad2/3 phosphorylation and relieved chronic kidney disease-promoted AVF failure independent of macrophages. Conclusions Our findings suggest that NLRP 3 in vascular smooth muscle cells may play a crucial role in uremia-associated AVF failure and may be a promising therapeutic target for the treatment of AVF failure.