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Oxidative stress by monosodium urate crystals promotes renal cell apoptosis through mitochondrial caspase-dependent pathway in human embryonic kidney 293 cells: mechanism for urate-induced nephropathy

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Abstract

The aim of this study is to clarify the effect of oxidative stress on monosodium urate (MSU)-mediated apoptosis of renal cells. Quantitative real-time polymerase chain reaction and immunoblotting for Bcl-2, caspase-9, caspase-3, iNOS, cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), IL-18, TNF receptor-associated factor-6 (TRAF-6), and mitogen-activated protein kinases were performed on human embryonic kidney 293 (HEK293) cells, which were stimulated by MSU crystals. Fluorescence-activated cell sorting was performed using annexin V for assessment of apoptosis. Reactive oxygen species (ROS) were measured. IL-1β siRNA was used for blocking IL-1β expression. MSU crystals promoted ROS, iNOS, and COX-2 expression and also increased TRAF-6 and IL-1β expression in HEK293 cells, which was inhibited by an antioxidant ascorbic acid. Caspase-dependent renal cell apoptosis was induced through attenuation of Bcl-2 and enhanced caspase-3 and caspase-9 expression by MSU crystals, which was significantly reversed by ascorbic acid and transfection of IL-1β siRNA to HEK293 cells. Ascorbic acid inhibited phosphorylation of extracellular signal-regulated kinase and Jun N-terminal protein kinase stimulated by MSU crystals. ROS accumulation and iNOS and COX-2 mRNA expression by MSU crystals was also suppressed by transfection with IL-1β siRNA. Oxidative stress generated by MSU crystals promotes renal apoptosis through the mitochondrial caspase-dependent apoptosis pathway.

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Acknowledgments

This work was supported by a grant from the Research Institute of Medical Science, Catholic University of Daegu (2013).

Conflict of interest

The authors do not have an actual or potential conflict of interest or not get interest of any kind to declare with regard to this work.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, 33, Duryugongwon-ro 17-gil, Nam-gu, Daegu, 705-718, Republic of Korea

    Jung-Yoon Choe & Seong-Kyu Kim

  2. Arthritis and Autoimmunity Research Center, Catholic University of Daegu, Daegu, Republic of Korea

    Jung-Yoon Choe, Ki-Yeun Park & Seong-Kyu Kim

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  1. Jung-Yoon Choe
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Correspondence to Seong-Kyu Kim.

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Choe, JY., Park, KY. & Kim, SK. Oxidative stress by monosodium urate crystals promotes renal cell apoptosis through mitochondrial caspase-dependent pathway in human embryonic kidney 293 cells: mechanism for urate-induced nephropathy. Apoptosis 20, 38–49 (2015). https://doi.org/10.1007/s10495-014-1057-1

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