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p-Cresyl sulfate, a uremic toxin, causes vascular endothelial and smooth muscle cell damages by inducing oxidative stress.

Watanabe H, Miyamoto Y, Enoki Y, Ishima Y, Kadowaki D, Kotani S, Nakajima M, Tanaka M, Matsushita K, Mori Y, Kakuta T, Fukagawa M, Otagiri M, Maruyama T - Pharmacol Res Perspect (2014)

Bottom Line: In HASMC, PCS increased the mRNA levels of alkaline phosphatase (ALP), osteopontin (OPN), core-binding factor alpha 1, and ALP activity.The vascular damage induced by PCS was largely suppressed in the presence of probenecid, an inhibitor of organic anion transporters (OAT).In PCS-overloaded 5/6-nephrectomized rats, plasma MCP-1 levels, OPN expression, and ALP activity of the aortic arch were increased, accompanied by the induction of Nox4 expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University Kumamoto, Japan ; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University Kumamoto, Japan.

ABSTRACT
The major cause of death in patients with chronic kidney disease (CKD) is cardiovascular disease. Here, p-Cresyl sulfate (PCS), a uremic toxin, is considered to be a risk factor for cardiovascular disease in CKD. However, our understanding of the vascular toxicity induced by PCS and its mechanism is incomplete. The purpose of this study was to determine whether PCS enhances the production of reactive oxygen species (ROS) in vascular endothelial and smooth muscle cells, resulting in cytotoxicity. PCS exhibited pro-oxidant properties in human umbilical vein endothelial cells (HUVEC) and aortic smooth muscle cells (HASMC) by enhancing NADPH oxidase expression. PCS also up-regulates the mRNA levels and the protein secretion of monocyte chemotactic protein-1 (MCP-1) in HUVEC. In HASMC, PCS increased the mRNA levels of alkaline phosphatase (ALP), osteopontin (OPN), core-binding factor alpha 1, and ALP activity. The knockdown of Nox4, a subunit of NADPH oxidase, suppressed the cell toxicity induced by PCS. The vascular damage induced by PCS was largely suppressed in the presence of probenecid, an inhibitor of organic anion transporters (OAT). In PCS-overloaded 5/6-nephrectomized rats, plasma MCP-1 levels, OPN expression, and ALP activity of the aortic arch were increased, accompanied by the induction of Nox4 expression. Collectively, the vascular toxicity of PCS can be attributed to its intracellular accumulation via OAT, which results in an enhanced NADPH oxidase expression and increased ROS production. In conclusion, we found for the first time that PCS could play an important role in the development of cardiovascular disease by inducing vascular toxicity in the CKD condition.

No MeSH data available.


Related in: MedlinePlus

Effect of PCS on the mRNA expression of ALP, OPN, Cbfa1 and the ALP activity in HASMC: The mRNA levels corresponding to (A) ALP, (B) OPN and (C) Cbfa1 in HASMC were normalized against 18S ribosomal RNA in the absence or presence of 1000 μmol/L probenecid. The results are shown as the fold in expression as compared to control (0 μmol/L PCS) (mean ± SD, n = 4, **P < 0.01 vs. control; ##P < 0.01 vs. PCS). (D) ALP activity was determined in the absence or presence of 1000 μmol/L probenecid. (mean ± SD, n = 6, **P < 0.01 vs. control, ##P < 0.01 vs. PCS). HASMC was incubated with 1000 μmol/L PCS at 37°C for (A, B and C) 24 h and (D) 48 h.
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fig04: Effect of PCS on the mRNA expression of ALP, OPN, Cbfa1 and the ALP activity in HASMC: The mRNA levels corresponding to (A) ALP, (B) OPN and (C) Cbfa1 in HASMC were normalized against 18S ribosomal RNA in the absence or presence of 1000 μmol/L probenecid. The results are shown as the fold in expression as compared to control (0 μmol/L PCS) (mean ± SD, n = 4, **P < 0.01 vs. control; ##P < 0.01 vs. PCS). (D) ALP activity was determined in the absence or presence of 1000 μmol/L probenecid. (mean ± SD, n = 6, **P < 0.01 vs. control, ##P < 0.01 vs. PCS). HASMC was incubated with 1000 μmol/L PCS at 37°C for (A, B and C) 24 h and (D) 48 h.

Mentions: To examine the effect of PCS on the osteogenic differentiation of vascular smooth muscle cells, the effect of PCS on the expression of ALP, OPN, and Cbfa1, which are osteoblast-specific proteins, in HASMC was investigated. As shown in Figure4A–C, a 24 h incubation of HASMC with 1000 μmol/L PCS resulted in a significant increase in the mRNA levels of ALP, OPN, and Cbfa1. Furthermore, PCS significantly increased ALT activity in HASMC (24 h incubation) (Fig.4D). These effects of PCS were suppressed to the control level in the presence of probenecid.


p-Cresyl sulfate, a uremic toxin, causes vascular endothelial and smooth muscle cell damages by inducing oxidative stress.

Watanabe H, Miyamoto Y, Enoki Y, Ishima Y, Kadowaki D, Kotani S, Nakajima M, Tanaka M, Matsushita K, Mori Y, Kakuta T, Fukagawa M, Otagiri M, Maruyama T - Pharmacol Res Perspect (2014)

Effect of PCS on the mRNA expression of ALP, OPN, Cbfa1 and the ALP activity in HASMC: The mRNA levels corresponding to (A) ALP, (B) OPN and (C) Cbfa1 in HASMC were normalized against 18S ribosomal RNA in the absence or presence of 1000 μmol/L probenecid. The results are shown as the fold in expression as compared to control (0 μmol/L PCS) (mean ± SD, n = 4, **P < 0.01 vs. control; ##P < 0.01 vs. PCS). (D) ALP activity was determined in the absence or presence of 1000 μmol/L probenecid. (mean ± SD, n = 6, **P < 0.01 vs. control, ##P < 0.01 vs. PCS). HASMC was incubated with 1000 μmol/L PCS at 37°C for (A, B and C) 24 h and (D) 48 h.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317224&req=5

fig04: Effect of PCS on the mRNA expression of ALP, OPN, Cbfa1 and the ALP activity in HASMC: The mRNA levels corresponding to (A) ALP, (B) OPN and (C) Cbfa1 in HASMC were normalized against 18S ribosomal RNA in the absence or presence of 1000 μmol/L probenecid. The results are shown as the fold in expression as compared to control (0 μmol/L PCS) (mean ± SD, n = 4, **P < 0.01 vs. control; ##P < 0.01 vs. PCS). (D) ALP activity was determined in the absence or presence of 1000 μmol/L probenecid. (mean ± SD, n = 6, **P < 0.01 vs. control, ##P < 0.01 vs. PCS). HASMC was incubated with 1000 μmol/L PCS at 37°C for (A, B and C) 24 h and (D) 48 h.
Mentions: To examine the effect of PCS on the osteogenic differentiation of vascular smooth muscle cells, the effect of PCS on the expression of ALP, OPN, and Cbfa1, which are osteoblast-specific proteins, in HASMC was investigated. As shown in Figure4A–C, a 24 h incubation of HASMC with 1000 μmol/L PCS resulted in a significant increase in the mRNA levels of ALP, OPN, and Cbfa1. Furthermore, PCS significantly increased ALT activity in HASMC (24 h incubation) (Fig.4D). These effects of PCS were suppressed to the control level in the presence of probenecid.

Bottom Line: In HASMC, PCS increased the mRNA levels of alkaline phosphatase (ALP), osteopontin (OPN), core-binding factor alpha 1, and ALP activity.The vascular damage induced by PCS was largely suppressed in the presence of probenecid, an inhibitor of organic anion transporters (OAT).In PCS-overloaded 5/6-nephrectomized rats, plasma MCP-1 levels, OPN expression, and ALP activity of the aortic arch were increased, accompanied by the induction of Nox4 expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University Kumamoto, Japan ; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University Kumamoto, Japan.

ABSTRACT
The major cause of death in patients with chronic kidney disease (CKD) is cardiovascular disease. Here, p-Cresyl sulfate (PCS), a uremic toxin, is considered to be a risk factor for cardiovascular disease in CKD. However, our understanding of the vascular toxicity induced by PCS and its mechanism is incomplete. The purpose of this study was to determine whether PCS enhances the production of reactive oxygen species (ROS) in vascular endothelial and smooth muscle cells, resulting in cytotoxicity. PCS exhibited pro-oxidant properties in human umbilical vein endothelial cells (HUVEC) and aortic smooth muscle cells (HASMC) by enhancing NADPH oxidase expression. PCS also up-regulates the mRNA levels and the protein secretion of monocyte chemotactic protein-1 (MCP-1) in HUVEC. In HASMC, PCS increased the mRNA levels of alkaline phosphatase (ALP), osteopontin (OPN), core-binding factor alpha 1, and ALP activity. The knockdown of Nox4, a subunit of NADPH oxidase, suppressed the cell toxicity induced by PCS. The vascular damage induced by PCS was largely suppressed in the presence of probenecid, an inhibitor of organic anion transporters (OAT). In PCS-overloaded 5/6-nephrectomized rats, plasma MCP-1 levels, OPN expression, and ALP activity of the aortic arch were increased, accompanied by the induction of Nox4 expression. Collectively, the vascular toxicity of PCS can be attributed to its intracellular accumulation via OAT, which results in an enhanced NADPH oxidase expression and increased ROS production. In conclusion, we found for the first time that PCS could play an important role in the development of cardiovascular disease by inducing vascular toxicity in the CKD condition.

No MeSH data available.


Related in: MedlinePlus