Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease

Abstract

of the Rodent Metabolic Phenotyping core facility of the CRCHUM for metabolic studies in mice; M. Guévremont, J. Morin, and the Cellular Physiology Service core of the CRCHUM for quantification of β cell mass and αLISA assay; C. Tremblay (CRCHUM) for valuable technical assistance; E. Joly for technical advice; and M. Ferdaoussi for fruitful discussions.Address correspondence to: Vincent Poitout, CRCHUM, 900 Saint-Denis Street, Montreal, Quebec, H2X 0A9, Canada. Phone: 514.890.8044; E-mail: vincent.poitout@umontreal.ca.the CHUM (protocols ND-05-035 and 16-048, respectively). Written consent for research was obtained from all donors.

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

“…Koppe et al (44) demonstrated that urea could also directly impair pancreatic β-cell function. Exposure of mouse and human islets to urea concentrations seen in the very early stage of renal failure increased islet protein O-GlcNAcylation, causing inhibition of glycolysis and, consequently, impaired insulin secretion (44).…”

“…Similarly, insulin secretion was impaired in normal mice treated orally with urea for 3 weeks and it was restored by inhibition of O-GlcNAcylation (44). 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.…”

“…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).…”

“…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).…”

“…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). Oxidative stress is common in patients with CKD, and reduction of oxidative stress has a number of beneficial effects (45).…”