Uremia, Angioplasty Injury, and Vessel Type (Artery vs. Vein) Activate Differential Gene Expression and Pathway Profiles

Background: Patients with CKD and ESKD suffer from aggressive dialysis vascular access stenosis within the venous segment of AVFs and AVGs. They also suffer from a huge burden of vascular disease, which responds poorly to interventions such as angioplasty. Despite the huge morbidity, mortality, and economic costs associated with both dialysis vascular access dysfunction and peripheral vascular disease in CKD and ESKD patients, the pathogenetic pathways responsible for this remain unclear. Methods: Pigs were made uremic by performing a right sided nephrectomy followed by a selective ligation of the branches of the left renal artery. After 2 weeks of uremic condition, we performed an angioplasty of the femoral artery and vein on one side, with the contralateral side serving as a control. Animals were sacrificed two weeks post angioplasty, and arterial and venous samples from the femoral artery and vein on both sides were collected for RNA extraction and bulk RNA sequencing. An identical set of experiments was performed on a non-uremic pig. Results: Differential expression gene analysis revealed that uremia up-regulated 21 genes in the control artery but only 7 genes in the control vein. In contrast, 177 genes were up-regulated in injured vein but only 1 gene was up-regulated in injury artery. In addition, the injury up-regulated 510 genes in normal vein but only 56 genes in normal artery. Additional pathway enrichment studies revealed differentially enriched pathways in different groups. For example, olfactory receptor activity, positive regulation of immune system process and interferon gamma response were the 3 maximally enriched pathways in uremic control artery whereas neuropeptide receptor activity, neuropeptide signaling pathway and molecular transducer activity were the 3 maximally enriched pathways in uremic control vein. Conclusion: Our results suggest that all three variables, uremia, angioplasty injury, and vessel type contribute to the differential gene expression and pathway analyses. Our data suggests that the optimal therapy to reduce restenosis following angioplasty of the venous segment of an AVF in an ESKD may be very different from that needed to reduce restenosis following arterial angioplasty injury in a CKD/ESKD patient.