4-cresol-sulfate and acetovanillone

p-Cresyl sulfate (PCS) is a risk factor of cardiovascular disease in patients with chronic kidney disease. Here we tested whether serum PCS levels were related to the rate and evolution of carotid atherosclerosis in hemodialysis patients and identified a potential mechanism. A total of 200 hemodialysis patients were categorized as with or without carotid atherosclerotic plaque and followed for 5 years. Serum PCS levels were found to be higher in patients with than without carotid atherosclerotic plaque and positively correlated with increased total plaque area during follow-up. Multiple logistic regression and mixed effects model analyses showed that serum PCS levels were independently associated with the incidence and progression of carotid atherosclerotic plaque. PCS induced inflammatory factor and adhesion molecule expression in endothelial cells and macrophages. In addition, PCS triggered monocyte-endothelial cell interaction in vitro and in vivo through increased production of reactive oxygen species. Compared with controls, increase of PCS levels produced by gavage promoted atherogenesis in 5/6-nephrectomized apoE-/- mice; a process attenuated by NADPH oxidase inhibitors. Thus, increased serum PCS levels are associated with the occurrence and progression of carotid atherosclerosis in hemodialysis patients and promote atherogenesis through increased reactive oxygen species production.

Topics: Acetophenones; Adult; Aged; Animals; Aorta; Apolipoproteins E; Carotid Artery Diseases; Case-Control Studies; Cresols; Disease Progression; Endothelial Cells; Female; Humans; Kidney Failure, Chronic; Macrophages; Male; Mice; Middle Aged; NADPH Oxidases; Reactive Oxygen Species; Sulfuric Acid Esters

Cardiovascular disease is the leading cause of death in patients with chronic kidney disease. A body of evidence suggests that p-cresyl sulfate (PCS), a uremic toxin, is associated with the cardiovascular mortality rate of patients with chronic kidney disease; however, the molecular mechanisms underlying this feature have not yet been fully elucidated.. We aimed to determine whether PCS accumulation could adversely affect cardiac dysfunction via direct cytotoxicity to cardiomyocytes. In mice that underwent 5/6 nephrectomy, PCS promoted cardiac apoptosis and affected the ratio of left ventricular transmitral early peak flow velocity to left ventricular transmitral late peak flow velocity (the E/A ratio) observed by echocardiography (n=8 in each group). Apocynin, an inhibitor of NADPH oxidase activity, attenuates this alteration of the E/A ratio (n=6 in each group). PCS also exhibited proapoptotic properties in H9c2 cells by upregulating the expression of p22(phox) and p47(phox), NADPH oxidase subunits, and the production of reactive oxygen species. Apocynin and N-acetylcysteine were both able to suppress the effect of PCS, underscoring the importance of NADPH oxidase activation for the mechanism of action.. This study demonstrated that the cardiac toxicity of PCS is at least partially attributed to induced NADPH oxidase activity and reactive oxygen species production facilitating cardiac apoptosis and resulting in diastolic dysfunction.

Topics: Acetophenones; Animals; Apoptosis; Blotting, Western; Cardiovascular Diseases; Caspase 3; Cells, Cultured; Cresols; Echocardiography; Male; Mice; Mice, Inbred C57BL; Myocardium; Myocytes, Cardiac; Reactive Oxygen Species; Renal Insufficiency, Chronic; Sulfuric Acid Esters; Ventricular Function, Left