Role of the Mineralocorticoid Receptor in Hemodialysis Vascular Access Dysfunction

Background: Vascular access stenosis is a major complication in dialysis patients, primarily occurring at the venous anastomosis site. While the role of the mineralocorticoid receptor (MR) has been well characterized in the heart and large arteries, its function in venous cells remains unclear. This study aims to investigate MR expression and activation pathways in venous endothelial cells (ECs) and smooth muscle cells (SMCs), and to evaluate the inhibitory effects of MR antagonists (MRAs). Methods: Human umbilical vein endothelial cells (HUVECs) and venous SMCs were cultured and treated with the MR agonist aldosterone, as well as the MRAs spironolactone and finerenone. MR expression, SMC proliferation, oxidative stress, and inflammatory signaling pathways (MAPK, ERK1/2, NF-κB) were assessed by Western blot, RT-PCR, and ROS assays. The effects of pro-inflammatory stimuli (TNF-α) and the uremic toxin indoxyl sulfate on MR activation were also evaluated, along with the potential suppressive roles of MRAs and antioxidants (N-acetyl cysteine, probenecid). Results: MR expression was upregulated in both HUVECs and SMCs upon aldosterone stimulation and was significantly suppressed by spironolactone and finerenone. MR activation was associated with increased SMC proliferation, oxidative stress, and activation of inflammatory pathways. TNF-α and indoxyl sulfate induced MR expression and inflammatory marker upregulation, which were attenuated by MRAs and antioxidants. Conclusion: MR activation in venous ECs and SMCs promotes SMC proliferation, oxidative stress, and inflammation, contributing to vascular access stenosis. The non-steroidal MRA finerenone effectively attenuates these processes and may serve as a promising therapeutic strategy to prevent vascular access failure in dialysis patients. Funding: Private Foundation Support