Mechanisms of Oxidative Stress an d Vessels Sclerotic Transformation Initiated by Uremic Toxin Indoxyl Sulfate

Abstract

<p> The microspherical carbonaceous adsorbents SCN and AST-120 for oral use prevent chronic disease progression, delay dialysis initiation, lessen atherosclerosis development in kidney and decreased of overall and cardiovascular mortality. This therapeutic effect is due to the binding of indole by sorbents in large intestine, which is a precursor of indoxyl sulfate (IS). It is considered that IS accelerates the progression of chronical kidney disease (CKD) by inducing a formation of reactive oxygen species (ROS) and promotes aortic calcification (mineralization). Molecular mechanisms of IS action is unknown. Using density functional theory calculations in the frames of B3LYP exchange and correlation functional (basis set 6-311G) and solvation accounting on the base of polarizable continuum model (PCM) we have studied some chemical transformations of IS and have shown a possibility of indoxyl sulfate and hydroperoxyl radicals formation through the reaction of IS with endogenous singlet oxygen. Due to the high activity indoxyl sulfate radicals initiate uncontrollable processes of oxidative stress (OS) in kidney and vascular tissues that promote a development of CKD. We also proposed a hypothesis, which can explain the role of OS in the accelerated development of sclerosis (vessels mineralization) in patients with renal diseases. In particular it was hypothesized and then supported by B3LYP/6-311G(d) + PCM calculations that sulfonic groups (products of deep oxidation of thiol groups in tissue proteins under OS, induced by IS) can selectively bind of Ca²⁺ ions and, consequently, forming RSO₃Ca⁺ groups which can fix НРО₄^2ˉ and CO₃^2ˉ anions. The products of anions fixation can then bind of Ca2+ ions, etc. Notably, these processes are, probably, primary starting point in case of sclerotic vessel changes. The beginning of this starting mineralization process most likely is possible with proteins carboxyl groups forming under OS that also can bind Ca²⁺.</p>