Mineralocortidoid Receptor Mediates Uremic Serum‐Induced Increase in Endothelial Cell Dysfunction

Abstract

Patients with chronic kidney disease (CKD) have a markedly increased incidence of cardiovascular disease (CVD) and mortality compared with the age‐matched general population. The high concentration of circulating uremic toxins in CKD patients leads to vascular inflammatory, thereby inducing endothelial dysfunction, which is associated with CVD development and progression. Plasma aldosterone levels are increased in CKD, and aldosterone has been found to increase vascular inflammation and fibrosis. The aim of our study was to analyze the influence of CKD in the expression of endothelial ion channels and its potential modification by mineralocorticoid receptor (MR) inhibition, which would consequently affect endothelial cell function. To that end we used primary human endothelial cells cultured in medium supplemented with pooled sera from either healthy or uremic patients undergoing dialysis. To obtain a complete profile of ion channel subunit expression in both cellular types, we performed high‐throughput qPCR of 92 ion channel genes using a custom‐designed Taqman low‐density array card. In addition, we characterized the influence of uremic serum on nitric oxide (NO) production and measured cortical stiffness using atomic force microscopy. Our data show that uremic serum potently increased MR expression. In addition, it induced remodeling of ion channel expression patterns, including increased expression of αENaC, a known transcriptional target of MR that promotes cortical stiffness and endothelial dysfunction. Exposure of endothelial cells to uremic serum significantly decreased NO production and produced stiffening of the endothelial cell cortex, which was prevented by inhibition of MR using spironolactone. Our data identifies MR as a possible mediator of uremia‐induced endothelial dysfunction and supports the proposed beneficial effects of MR inhibition during CKD.Support or Funding InformationThis work was supported by a grant from Ministerio de Economía e Innovación (MINECO, grant BFU2016‐78374‐R) to D.A.R.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.