Protein-bounded uremic toxin p-cresylsulfate induces vascular permeability alternations
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The goal of the present studies is to investigate that the impact of p-cresylsulfate (PCS) on the endothelial barrier integrity via in situ exposure and systemic exposure. Vascular permeability changes induced by local injection of PCS were evaluated by the techniques of both Evans blue (EB) and India ink tracer. Rats were intravenously injected with EB or India ink followed by intradermal injections of various doses of PCS (0, 0.4, 2, 10 and 50 µmol/site) on rat back skins. At different time points, skin EB was extracted and quantified. The administration of India ink was used to demonstrate leaky microvessels. Skin PCS levels were also determined by liquid chromatography–mass spectrometry. We also investigated whether the increased endothelial leakage occurred in the aortic endothelium in rats treated with 5/6 nephrectomy and intraperitoneal injection of PCS 50 mg/kg/day for 4 weeks. The aortic endothelial integrity was evaluated by increased immunoglobulin G (IgG) leakage. High doses of PCS, but not lower doses, significantly induced vascular leakage as compared to saline injection and EB leakage exhibited in time-dependent manner. A time-correlated increase in leaky microvessels was detected in the tissues examined. The injected PCS declined with time and displayed an inverse relationship with vascular leakage. Chronic kidney disease (CKD) rats administered with PCS, compared to control rats, had significantly higher serum levels of PCS and apparent IgG deposition in the aortic intima. Increased endothelial leakage induced by PCS in skin microvessels and the aorta of CKD rats suggests that the PCS-induced endothelial barrier dysfunction.
Keywordsp-Cresylsulfate Vascular permeability Vascular leakage Chronic kidney disease Endothelial dysfunction Aortic endothelium
This work was supported by grants from Ministry of Science and Technology, Taiwan, R.O.C. (MOST 104-2320-B-037-016 and MOST 105-2314-B-010-061) and National Yang-Ming University Hospital (RD 2017-008). We acknowledge the laboratory technique service of histology (including image digitizing of virtual slides) and pathology at Litzung Biotechnology INC., Kaohsiung, Taiwan. All tissue sections of CKD model rats were analyzed and scored by the experienced veterinary pathologist, Hao-Kai Chang (Litzung Biotechnology INC.).
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Conflict of interest
The author declares that they have no conflict of interest.
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