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

  • V. Strelko Institute for Sorption and Problems of Endoecology, General Naumov str.13, Kiev 03164, Ukraine
  • Yu. Gorlov Institute for Sorption and Problems of Endoecology, General Naumov str.13, Kiev 03164, Ukraine
Keywords: carbon oral sorbents; chronic kidney disease; uremic and cardiovascular toxins; indoxyl sulfate; free radicals; oxidative stress; density functional theory; aortic calcification.


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 and CO3 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+.


[1]. S.I. Ryabov, G.D. Shostka, B.G. Lukichev, and V.V. Strelko, Intern. Urology and Nephrology 16 (1984) 345–360.

[2]. G.D. Shostka, S.I. Ryabov, B.G. Lukichev, and V.V. Strelko, Therapeutic archive 56 (1984) 58–63 (in Russian).

[3]. V.G. Nikolaev, and V.V. Strelko, Hemosorption on activated carbons (Russ.), Kiev: Naukova dumka, (1979)
287 p.

[4]. V.V. Strelko. Intern. Conf. Carbon 90, France, Paris. Extend. Abstr. (1990) 16–17.

[5]. B.G. Lukichev, G.D. Shostka, V.V. Strelko, T.S. Azizova, Yu.R. Kavrayski, and I.Yu. Panina, Soviet Archives of Internal Medicine 64 (1992) 501–504.

[6]. T. Niwa, Y. Emoto, K. Maeda, Y. Uehara, M. Yamada, and M. Shibata, Nephrol. Dial. Transplant. 6 (1991) 105–109.

[7]. T. Niwa, Nagoya J. Med. Sci. 72 (1-2) (2010) 1–11.

[8]. T. Niwa, Uremic toxins (2012) Wiley&Suns.

[9]. C.-K. Chiang, T. Tanaka, and M. Nangaku, J. Renal Nutr. 22 (1) (2012) 77–80.

[10]. A.K. Gelasco, and J.R. Raymond, Am. J. Physiol. Renal Physiol. 290 (6) (2006) F1551-F1558.

[11]. M.W. Schmidt, K.K. Baldridge, J.A. Boatz et al, J. Comput. Chem. 14 (11) (1993) 1347–1363.

[12]. J. Tomasi, B. Mennucci, and R. Cammi, Chem. Rev. 105 (8) (2005) 2999–3093.

[13]. T. Eicher, and S. Hauptmann, The chemistry of heterocycles. Structure, reactions, synthesis, and applications. Second ed., Wiley-VCH GmbH&Co. KGaA, Germany (2003) 556 p.

[14]. N.N. Greenwood, and A. Earnshaw, Chemistry of elements. Second ed., Butterworth-Heinemann, Oxford, England (1998) 1304 p.

[15]. M.J. Steinbeck, A.U. Khan, and M.J. Karnovsky, J. Biol. Chem. 267 (19) (1992) 13425–13433.

[16]. R.E. Lynch, and I. Fridovich, Biochim. Biophys. Acta 571 (2) (1979) 195–200.

[17]. E.J. Corey, M.M. Mehrotra, and A.U. Khan, Biochem. Biophys. Res. Commun. 145 (2) (1987) 842–846.

[18]. V.A. Kostiuk, and A.I. Potapovich, Bioradicals and Bioantioxidants (Russ.), Belarusian State University Publishing House, Minsk, Belarus, (2004) 174 p.

[19]. M.D. Carbonare, and M.A.Pathak, J. Photochem. Photobiol. B 30 (1-3) (1992) 105–124.

[20]. H. Sies, and C.F.M. Menck, Mutation Res. 275 (3-6) (1992) 367–376.

[21]. J.S. Zigler, J.D.Goosey, Photochem. Photobiol. 33 (6) (1981) 869–874.

[22]. R.C. Kukreja, M.L. Hess, Cardiovascular Res. 26 (6) (1992) 641–655.

[23]. Y. Miyamoto, Y. Iwao, Y. Tasaki, K. Sato, Y. Ishima, H. Watanabe, D. Kadawaki, and T. Maruyama, M. Otagiri, FEBS Letts. 584 (13) (2010) 2816–2820.

[24]. J.M. Gebicki, and H.J. Bielski, J. Am. Chem. Soc. 103 (23) (1981) 7020–7022.

[25]. Lange’s Handbook of Chemistry, fifteenth ed. McGraw-Hill Inc., New York et al. (1999) 1561 p.

[26]. B. Plesničar, Acta Chim. Sloven. 52 (1) (2005) 1–12.

[27]. X. Xu, R.P. Muller, and W.A Goddard III, Proc. Natl. Acad. Sci. USA, 99 (6) (2002) 3376–3381.

[28]. X. Xu, and W.A. Goddard III, Proc. Natl. Acad. Sci. USA 99.(23) (2002) 15308–15312.

[29]. A.D. Wenworth, L.H. Jones, P. Wenworth, K.D. Jauda, and R.A. Lerner, Proc. Natl. Acad. Sci. USA 97 (20) (2002) 10930–10935.

[30]. M.J. Davies, Biochim. Biophys. Acta 1703 (2) (2005) 93–109.

[31]. L. Turell, S. Carballal, H. Botti, R. Radi, and B. Alvarez, Braz. J. Med. Biol. Res. 42 (4) (2009) 305–311.

[32]. N.B. Kavuçkuoglu, Q. Li, N. Pleshko, and J. Uitto, Matrix Biol. 31 (4) (2012) 246–252.

[33]. C.Y. Lin, and D.W.Morel, J. Lipid Res. 42 (13) (2003) 3949–3955.

[34]. J.X. Rong, S. Rangaswamy, S. Lijang, R. Dave, Y. Chtang, H. Peterson, H.N. Hodis, G.M. Chisolm, M. Guy, and A. Sevanian, Arterioscler. Thromb. Vascular Biol. 18 (12) (1998) 1885–1894.

[35]. A.J. Salinas, and M. Vallet-Regi, RSC Adv. 3 (28) (2013) 11116–11131.
How to Cite
V. Strelko and Y. Gorlov, “Mechanisms of Oxidative Stress an d Vessels Sclerotic Transformation Initiated by Uremic Toxin Indoxyl Sulfate”, Eurasian Chem. Tech. J., vol. 18, no. 1, pp. 39-45, Jan. 2016.