Sulfasalazine Prevents Arteriovenous Fistula Failure and Inhibits Endothelial-Mesenchymal Transition

Abstract

INTRODUCTION: Arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis; however, up to 60% fail within one year due to aggressive neointimal hyperplasia that is characterized by inflammation. Sulfasalazine is an anti-inflammatory drug that is used to treat inflammatory diseases. We hypothesized that sulfasalazine suppresses neointimal hyperplasia by inhibition of TGF-β signaling. METHODS: Aortocaval AVF were created in C57BL/6J mice, with control mice having sham procedures. CKD was created via 5/6 nephrectomy (Nx), with control mice having no (0/6) nephrectomy, three weeks prior to AVF operation. CKD mice with AVF were divided into two groups with or without sulfasalazine treatment. AVF diameter was determined using ultrasound at postoperative days 7, 14, and 21. AVF were harvested at days 7 or 21 and examined with histology, Immunofluorescence and Western blot. RESULTS: AVF+5/6Nx had significantly increased wall thickness (p < 0.005) and increased TGF-β1 (p = 0.0217) compared to AVF+0/6Nx (day 21; n = 6; t-test). Endothelial cells in AVF+5/6Nx had significantly increased immunoreactivity of the mesenchymal markers notch3 (p < 0.005), vimentin (p < 0.005) and FSP-1 (p = 0.0189; day 21; n = 6; t-test). The sulfasalazine treatment group had significantly decreased FSP-1 (p < 0.005), vimentin (p < 0.005); notch3 (p < 0.005; day 21; n = 6; t-test), consistent with reduced EndMT, as well as decreased wall thickness (p < 0.005;) and increased diameter (p < 0.05; t-test; day 21; n = 6-15). CONCLUSION: CKD promotes neointimal hyperplasia via EndMT during AVF maturation leading to AVF failure; Sulfasalazine could be a therapeutic drug to improve AVF maturation.