Abstract
p-cresol (PC) and p-cresyl sulfate (PCS) are responsible for many of the uremia clinical consequences, such as atherosclerosis in Chronic Kidney Disease (CKD) patients. We investigate the in vitro impact of PC and PCS on monocyte chemoattractant protein-1 (MCP-1) expression via NF-kappa B (NF-κB) p65 in VSMC. PCS was synthesized by PC sulfatation. VSMC were extracted by enzymatic digestion of umbilical cord vein and characterized by immunofluorescence against α-actin antibody. The cells were treated with PC and PCS at their normal (n), uremic (u) and maximum uremic concentrations (m). Cell viability was assessed by MTT. MCP-1 expression was investigated by ELISA in cells supernatants after toxins treatment with or without the NF-κB p65 inhibitor. There was no significant difference in cell viability after toxins treatment for all concentrations tested. There was a significant increase in MCP-1 expression in cells treated with PCu and PCm (p < 0.001) and PCSn, PCSu and PCSm (p < 0.001), compared with the control. When VSMC were treated with the NF-κB p65 inhibitor plus PCu and PCm, there was a significant decrease in MCP-1 production (p < 0.005). This effect was not observed with PCS. VSMC are involved in atherosclerosis lesion formation and production of MCP-1, which contributes to the inflammatory response initiation. Our results suggest that PC mediates MCP-1 production in VSMC, probably through NF-κB p65 pathway, although we hypothesize that PCS acts through a different subunit pathway since NF-κB p65 inhibitor was not able to inhibit MCP-1 production.
Highlights
The uremic toxin p-cresol (PC), 4-methylphenol (MW: 108.14 g/mol), is a low molecular weight uremic toxin with high affinity to proteins, originated from tyrosine and phenylalanine catabolism by intestinal microorganisms
vascular smooth muscle cells (VSMC) are involved in atherosclerosis lesion formation and production of monocyte chemoattractant protein-1 (MCP-1), which contributes to the inflammatory response initiation
Our results suggest that PC mediates MCP-1 production in VSMC, probably through NF-κB p65 pathway, we hypothesize that p-cresyl sulfate (PCS) acts through a different subunit pathway since NF-κB p65 inhibitor was not able to inhibit MCP-1 production
Summary
The uremic toxin p-cresol (PC), 4-methylphenol (MW: 108.14 g/mol), is a low molecular weight uremic toxin with high affinity to proteins, originated from tyrosine and phenylalanine catabolism by intestinal microorganisms. Previous studies observed that p-cresol circulates in very low concentrations, and it is metabolized to its conjugates (p-cresyl sulfate - PCS and p-cresyl glucoronidate - PCG) by the intestinal flora, during its passage through the colon and liver mucosa.[1,2] PCS is considered the effective toxin, due to its significantly circulated concentration and biochemical impact in the body.[3]. PC accumulation results in toxic in vitro and in vivo effects with potential clinical impact, since it is a major contributor to the development of uremic cardiovascular complications.[4] Dialysis therapies eliminate 70% of urea and creatinine and only 30% of PC after a 4 hours session.[5,6] This leads to progressive accumulation of PC that has been associated with increased vascular lesions, activation of leukocytes and negative impact on clinical outcome.[5] In healthy subjects, the plasma concentration of PC is approximately 0.6 mg/L, but increases significantly to 20.1 mg/L in the early stages of chronic kidney disease (CKD), and to 40.7 mg/L in advanced CKD. Serum levels of free and total PCS were elevated in advanced CKD stages; only free PCS seems to be a predictor of mortality in CKD.[2]
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