Abstract
Advanced glycation end products (AGEs) are compounds classified as uremic toxins in patients with chronic kidney disease that have several pro-inflammatory effects and are implicated in the development of cardiovascular diseases. To explore the mechanisms of AGEs–endothelium interactions through the receptor for AGEs (RAGE) in the PKC-β pathway, we evaluated the production of MCP-1 and VCAM-1 in human endothelial cells (HUVECs), monocytes, and a coculture of both. AGEs were prepared by albumin glycation and characterized by absorbance and electrophoresis. The effect of AGEs on cell viability was assessed with an MTT assay. The cells were also treated with AGEs with and without a PKC-β inhibitor. MCP-1 and VCAM-1 in the cell supernatants were estimated by ELISA, and RAGE was evaluated by immunocytochemistry. AGEs exposure did not affect cell viability, but AGEs induced RAGE, MCP-1, and VCAM-1 expression in HUVECs. When HUVECs or monocytes were incubated with AGEs and a PKC-β inhibitor, MCP-1 and VCAM-1 expression significantly decreased. However, in the coculture, exposure to AGEs and a PKC-β inhibitor produced no significant effect. This study demonstrates, in vitro, the regulatory mechanisms involved in MCP-1 production in three cellular models and VCAM-1 production in HUVECs, and thus mimics the endothelial dysfunction caused by AGEs in early atherosclerosis. Such mechanisms could serve as therapeutic targets to reduce the harmful effects of AGEs in patients with chronic kidney disease.
Highlights
The prevalence of chronic kidney disease (CKD) is growing exponentially, and the leading cause of death among patients with CKD is cardiovascular disease (CVD), with incidence five times greater in the CKD population than in the general population [1,2]
One of the main findings in the present study was that Advanced glycation end products (AGEs) induced receptor for AGEs (RAGE) activation, and this suggests that the interaction between AGEs and RAGE at the endothelium surface functions as a signal transduction receptor that leads to the activation of the PKC-β pathway
When U937 cells and endothelial cells were exposed to AGEs in a time-dependent manner, we observed an increase in the expression of the endothelial cell activation markers MCP-1 and VCAM-1
Summary
The prevalence of chronic kidney disease (CKD) is growing exponentially, and the leading cause of death among patients with CKD is cardiovascular disease (CVD), with incidence five times greater in the CKD population than in the general population [1,2]. The AGEs molecules may bind to collagen and elastin (which is primarily responsible for vascular elasticity) and accumulate in the matrix of blood vessels in a nonfunctional and disorderly manner; changes in endothelial vasomotor tone modulation, platelet adhesion, and cell proliferation may occur [12]. Another deleterious effect of AGEs as a uremic toxin is nitric oxide (NO). To better understand the mechanisms of AGEs-mediated acceleration of CVD in CKD patients, we employed an in vitro approach using human endothelial cells (i.e., HUVECs), U937 cells, and a coculture of HUVECs and U937 cells to investigate the effect of AGEs on the expression of MCP-1 and VCAM-1 and, on PKC-β activation (known to be involved in diverse cellular signaling pathways)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
