Urea-induced ROS accelerate senescence in endothelial progenitor cells

Vascular toxicity of urea, a new “old player” in the pathogenesis of chronic renal failure induced cardiovascular diseases

“…In endothelial cells and in EPCs, it has been found that urea increased ROS production through the activation of both mitochondrial and cytosolic ROS generating mechanisms. Inhibition of either resulted in the complete normalization of urea-induced ROS (19,28). These observations are consistent with the emerging concept of crosstalk between mitochondria and NADPH oxidases, the major cytosolic sources of superoxide in endothelial cells (47).…”

“…Children on hemodialysis also show a reduction in EPCs number (27). Recently, we reported that urea, in addition to inducing endothelial damages, also had a toxic effect on EPCs, causing EPC dysfunction (28). Urea at the concentration seen in the very early stage of renal failure, impaired the ability of EPCs isolated from a healthy donor to form endothelial cell colony forming units (EC-CFU), and to differentiate into CD31 and vascular endothelial growth factor receptor 2-positive cells (29).…”

“…Therefore, increased concentrations of urea, as seen in CRF, can also accelerate the atherosclerotic process by inducing both insulin resistance and impaired insulin secretion Urea Toxicity: mechanism of action Urea exerts its toxic action through reactive oxygen species (ROS) production. Elevated concentrations of urea have been described to increase intracellular ROS generation in various cells, such as vascular endothelial cells, VSMCs, renal tubular cells, adipocytes, and beta cells (19,28,34,42,44). Normalization of intracellular ROS levels prevented each of the described urea effects such endothelial cell and EPC dysfunctions, EPC senescence, adipocyte insulin resistance, and impaired insulin of beta cells (18,28,42,44).…”

“…Considering that the normal range of urea nitrogen in human blood or serum (BUN) is 5 to 20 mg/dL, or 1.8 to 7.1 mmol/L urea, we have shown that a small increase of urea concentration to 10 nmol/L in EPCs was already able to significantly increase ROS production. Ten nanomoles per liter is a urea concentration seen in the very early stage of CRF (28). Cellular ROS can be produced by both mitochondrial and cytosolic mechanisms (46).…”

“…Elevated concentrations of urea have been described to increase intracellular ROS generation in various cells, such as vascular endothelial cells, VSMCs, renal tubular cells, adipocytes, and beta cells (19,28,34,42,44). Normalization of intracellular ROS levels prevented each of the described urea effects such endothelial cell and EPC dysfunctions, EPC senescence, adipocyte insulin resistance, and impaired insulin of beta cells (18,28,42,44). Furthermore, in normal mice either infused or treated orally with urea, antioxidant molecules can both restore insulin sensibility and normalize insulin secretion (42,44).…”