Effect of Systemic 1α,25-Dihydroxyvitamin D3 on Ier3 Expression in a Murine Arteriovenous Fistula Model

Background: Arteriovenous fistulas (AVF) are the lifeline for patients with end stage kidney disease (ESKD). Upregulation of immediate early response gene 3 (Ier3, encoding IEX-1 protein) promotes venous neointimal hyperplasia (VNH) and venous stenosis leading to AVF failure. Local delivery of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) encapsulated in nanoparticles composed of PLGA in hydrogel to the outflow vein of AVFs in mice and pigs decreased Ier3 expression and VNH/VS. This study determined if systemic 1,25(OH)2D3 delivery can suppress Ier3 expression in a murine model of chronic kidney disease (CKD) with AVF. Methods: Eighteen C57BL/6J male mice, 6-8 weeks old, had CKD induced by performing left nephrectomy with upper pole ablation on the right. Twenty-eight days later, an AVF was placed to connect the end of the left common carotid artery to the side of the right external jugular vein and animals were randomized to vehicle, 50, 100, or 150 ng/kg/day of 1,25(OH)2D3 administered using a Alzet pump implanted subcutaneously. Seven days later, AVF outflow vein segments were harvested to assess for gene expression of Ier3 and Mcp-1 using qRT-PCR analysis. Serum 1,25(OH)2D3 levels, calcium levels, and vascular calcification of the inferior vena cava (IVC) was measured. Results: Systemic delivery of 1,25(OH)2D3 resulted in a dose-dependent increase in serum calcium levels, rising significantly from 10.23 ± 0.28 mg/dL (vehicle) to 13.57 ± 0.69 mg/dL at the highest dose (p < 0.02). Calcium deposition in the IVC increased with dose but was not significant. Serum 1,25(OH)2D3 levels at the highest dose (150 ng/kg/day) remained within the normal range. Ier3 gene expression levels in the AVF outflow veins were increased significantly with systemic treatment compared to control (P = 0.0136) with no difference in Mcp-1 expression. Conclusion: Systemic administration of 1α,25-dihydroxyvitamin D3 leads to increase in serum and vascular calcium levels without decreasing Ier3 expression. Funding: NIDDK Support - NIDDK Support, NIDDK Support