Passage Number-Induced Replicative Senescence Modulates the Endothelial Cell Response to Protein-Bound Uremic Toxins

Abstract

Endothelial aging may be induced early in pathological situations. The uremic toxins indoxyl sulfate (IS) and p-cresol (PC) accumulate in the plasma of chronic kidney disease (CKD) patients, causing accelerated endothelial aging, increased cardiovascular events and mortality. However, the mechanisms by which uremic toxins exert their deleterious effects on endothelial aging are not yet fully known. Thus, the aim of the present study is to determine the effects of IS and PC on endothelial damage and early senescence in cultured human umbilical vein endothelial cells (HUVECs). Hence, we establish an in vitro model of endothelial damage mediated by different passages of HUVECs and stimulated with different concentrations of IS and PC to evaluate functional effects on the vascular endothelium. We observe that cell passage-induced senescence is associated with apoptosis, ROS production and decreased endothelial proliferative capacity. Similarly, we observe that IS and PC cause premature aging in a dose-dependent manner, altering HUVECs’ regenerative capacity, and decreasing their cell migration and potential to form vascular structures in vitro. In conclusion, IS and PC cause accelerated aging in HUVECs, thus contributing to endothelial dysfunction associated with CKD progression.

The Effect of High-Flux Dialysis Combined with Hemoperfusion to Eliminate Indoxyl Sulfate in Dialysis Patients

“…Indoxyl Sulfate (IS) which a protein bound uremic toxin is derived from tryptophan and metabolized by bacteria in the gastrointestinal tract [10][11][12][13], More than 90% of IS in the blood binds to albumin. When kidney function is normal, Blood circulation of IS passes through the kidneys then excreted into urine [13][14].…”

miR-143-3p Promotes Ovarian Granulosa Cell Senescence and Inhibits Estradiol Synthesis by Targeting UBE2E3 and LHCGR

“…To investigate the role of miR-143-3p in GCs, we isolated primary GCs. These primary GCs can be passaged a limited number of times when cultured in vitro before entering a phase of irreversible growth arrest, known as replicative senescence, which is thought to reflect cellular aging in vivo [ 40 , 41 ]. We observed a significant and progressive increase in miR-143-3p expression in GCs with each cell passage.…”

Uremic Toxins Induce THP-1 Monocyte Endothelial Adhesion and Migration through Specific miRNA Expression

“…Working solutions were prepared by diluting the stock solution with culture medium in a 1:10 ( v / v ) ratio. PC was diluted in methanol to a final concentration of 0.0956 M. HUVECs and THP-1 cells were treated with IS (150 µg/mL) and PC (25 µg/mL) at concentrations within the reported uremic range as previously used in in vitro studies [ 53 ].…”