Citrate treatment reduces endothelial death and inflammation under hyperglycaemic conditions

Abstract

Hyperglycaemia and glucose degradation products (GDPs) are closely associated with oxidative stress and inflammation in diabetic patients, a condition that leads to endothelial dysfunction and cardiovascular problems. We evaluated the effect of citrate and gluconate on glucose- and GDP-induced endothelial inflammation by measuring changes in viability, inflammation and function in primary human umbilical vein endothelial cells (HUVECs). The extent of apoptosis/necrosis was measured by flow cytometry and visualised with confocal microscopy by staining with annexin V or propidium iodide, respectively. Protein kinase C-βII (PKC-βII) activation was evaluated with Western blotting. Incubation with glucose (30 mM) and GDP (50 µM) significantly increased PKC-βII expression, endothelial cell death and inflammation. The addition of citrate decreased hyperglycaemia-induced apoptosis (p = 0.021), necrosis (p = 0.04) and reduced PKC-βII expression (p = 0.021) down to background levels. Citrate improved endothelial function by reducing the inflammatory markers (p = 0.01) and by decreasing neutrophil diapedesis (p = 0.012). These results suggest that citrate may have therapeutic potential by reducing hyperglycaemia-induced endothelial inflammation and abolishing endothelial dysfunction.

Citrate versus Acetate-Based Dialysate in On-Line Haemodiafiltration. A Prospective Cross-Over Study

“…The dispensation of citrate per se reduces in vitro endothelial inflammation and death in a hyperglycemic environment [32]. In this study, CRP is lower after dialysis with citrate than at baseline and increases when acetate dialysate is used.…”

Citric Acid Effects on Brain and Liver Oxidative Stress in Lipopolysaccharide-Treated Mice

“…[11][12][13] In vitro, citrate improved endothelial function by reducing the inflammatory markers and decreasing neutrophil diapedesis in hyperglycemia. 14 Moreover, citric acid has been shown to reduce hepatocellular injury evoked in rats by carbon tetrachloride. 15 Citric acid might thus prove of value in decreasing oxidative stress.…”

Regional Citrate Anticoagulation for RRTs in Critically Ill Patients with AKI

“…Citrate anticoagulates the extracorporeal circuit by chelating ionized calcium (10,11,22), the key cofactor of many steps of the clotting cascade (23). Additional antihemostatic and anti-inflammatory activities of citrate may indirectly derive from its effects on blood cell components, including reduced activation of white blood cells and platelets (24)(25)(26)(27)(28)(29), and protective effects against endothelial-cell inflammation and dysfunction (30). Furthermore, citrate may be directly involved as a signal molecule in several cellular processes related to inflammation and balance of oxidative species (31).…”