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Mechanisms of inflammatory injury of renal tubular cells in a cellular model of pyelonephritis

  • Molecular and Cellular Mechanisms of Inflammation (Special Issue) Guest Editors S. A. Nedospasov and D. V. Kuprash
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Abstract

Previously, we have assembled a cellular model of pyelonephritis which contains a primary culture of renal tubular epithelial cells, mononuclear leukocytes, and bacterial lysate or lipopolysaccharide. After cocultivation of renal cells with leukocytes and bacterial lysate, proinflammatory changes were observed in the renal cells, followed by nitrosative and oxidative stress and cell death. The interaction of bacterial antigens not only with leukocytes, but also with epithelial cells of the renal tubules, was partially mediated by signaling pathways involving Toll-like receptors (TLR2 and TLR4). Activation of these receptors led to increased levels of oxidative stress and synthesis of proinflammatory cytokines (TNF, IL-6, IL-1α) in the renal epithelium, while TLR4 blockade decreased the severity of these processes. Apart from the fact that activation of inflammatory signaling in response to bacterial antigens is observed directly in the renal cells, the presence of leukocytes significantly amplifies the inflammatory response as measured by the level of cytokines generated in the ensemble. In the presence of activated leukocytes, higher expression of TLR2 on the surface of renal cells was observed in response to exposure to bacterial components, which might explain the increased inflammatory response in the presence of leukocytes. The synthesis of IL-1α in the epithelial cells of the renal tubules in this inflammatory model leads to its accumulation in the nuclei, which has been reduced by the TLR4 antagonist polymyxin. TLR2 agonists also led to increased levels of IL-1α. The elevation in the content of IL-1α in nuclei was accompanied by increased acetylation of nuclear proteins, which has been reduced to control values after exposure to protective agents (Trolox, mitochondria-targeted antioxidant SkQR1 or LiCl). The high level of acetylation of histones is probably regulated by proinflammatory cytokines, and to some extent it is a marker of inflammation, which can indirectly be reduced by protective agents.

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Abbreviations

DCF:

2,7-dihydrodichlorofluorescein

IL:

interleukin

LPS:

lipopolysaccharide

PBS:

phosphate-buffered saline

ROS:

reactive oxygen species

RTECs:

renal tubular epithelial cells

TLR:

Toll-like receptor

TNF:

tumor necrosis factor

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Authors and Affiliations

  1. Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991, Moscow, Russia

    M. A. Morosanova, V. A. Popkov & V. A. Babenko

  2. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    E. Y. Plotnikov, I. B. Pevzner, D. N. Silachev, S. S. Jankauskas & D. B. Zorov

  3. International Laser Center, Lomonosov Moscow State University, 119991, Moscow, Russia

    L. D. Zorova

Authors
  1. M. A. Morosanova
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  2. E. Y. Plotnikov
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  3. L. D. Zorova
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  4. I. B. Pevzner
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  5. V. A. Popkov
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  6. D. N. Silachev
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  7. S. S. Jankauskas
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  8. V. A. Babenko
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  9. D. B. Zorov
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Corresponding author

Correspondence to E. Y. Plotnikov.

Additional information

Original Russian Text © M. A. Morosanova, E. Y. Plotnikov, L. D. Zorova, I. B. Pevzner, V. A. Popkov, D. N. Silachev, S. S. Jankauskas, V. A. Babenko, D. B. Zorov, 2016, published in Biokhimiya, 2016, Vol. 81, No. 11, pp. 1481–1493.

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Morosanova, M.A., Plotnikov, E.Y., Zorova, L.D. et al. Mechanisms of inflammatory injury of renal tubular cells in a cellular model of pyelonephritis. Biochemistry Moscow 81, 1240–1250 (2016). https://doi.org/10.1134/S000629791611002X

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  • DOI: https://doi.org/10.1134/S000629791611002X

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