title: p-Cresyl sulfate, a uremic toxin, causes vascular endothelial and smooth muscle cell damages by inducing oxidative stress.
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.
authors.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.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University Kumamoto, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University Kumamoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Enoki
authors.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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ishima
authors.affiliation: Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University Kumamoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kadowaki
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University Kumamoto, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kotani
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University Kumamoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Department of Nephrology, Akebono Clinic Kumamoto, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Nephrology, Akebono Clinic Kumamoto, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine Kanagawa, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine Kanagawa, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kakuta
authors.affiliation: Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine Kanagawa, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Fukagawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University Kumamoto, Japan ; DDS Research Institute, Sojo University Kumamoto, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.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.
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
keywords: NADPH oxidase; oxidative stress; p-cresyl sulfate; uremic toxin; vascular damage