The uremic toxin indoxyl sulfate acts as a pro- or antioxidant on LDL oxidation

Abstract

Uremic toxins have been shown to play a role in chronic kidney disease (CKD) associated oxidative stress. Oxidative stress and inflammation have been associated with increased risk of cardiovascular disease in uraemia. The oxidative modification of LDL may play a role in early atherogenesis. Enhanced LDL oxidation has been found in uremic patients which may account for accelerated atherosclerosis observed in CKD. The uremic toxin indoxyl sulfate (IS) has been reported to exert oxidative and antioxidative activity. Thus, in the present study we have investigated the influence of IS on the atherogenic modifications of LDL exposed in vitro to different oxidising systems. The transition metal ion (Cu²⁺) and hemin/H₂O₂ induced lipid oxidation reactions monitored by conjugated diene formation, were inhibited by the presence of IS, which points to possible antioxidant effects by this uremic toxin. A protective effect of IS on LDL apoprotein modification by the exposure to the product of the myeloperoxidase/H₂O₂/Cl⁻ system HOCl, was also observed as estimated by protein carbonyl formation. In contrast, a marked increase in conjugated dienes and lipid hydroperoxides was observed when lipid oxidation was initiated by the free radical generator AAPH in presence of IS. The GC-MS analysis revealed the formation of indole-2,3-dione and 6,12-dihydro-6,12-dioxo-indolo[2,1-b]quinazoline (tryptanthrin) in IS/AAPH reaction. A scheme for the generation of tryptanthrin from IS via indoxyl radicals is proposed, which may facilitate LDL lipid oxidation. Our observations add further insight in the Janus-faced properties of this important uremic toxin.

Keywords::

• lipid oxidation
• hydrogen peroxide
• conjugated dienes
• chronic kidney disease
• tryptanthrin

Acknowledgement

The authors gratefully thank F. H. and Prof. Dr. Francesco Galli, Department of Internal Medicine, University of Perugia, Perugia, Italy, for helpful contributions preparing the manuscript and Prof. Dr. Norbert Haider, Department of Drug and Natural Product Synthesis, Faculty of Life Sciences, University of Vienna, Vienna, Austria, for valuable suggestions regarding the tryptanthrin reaction scheme.

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.

This work was supported by the Medical Scientific Fund of the Mayor of the City of Vienna (project BGM10059).