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Inflammatory Stress Exacerbated Mesangial Foam Cell Formation and Renal Injury via Disrupting Cellular Cholesterol Homeostasis

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Abstract

Inflammation and lipids play significant roles in the progression of chronic kidney disease. This study was designed to investigate whether inflammation disrupts cellular cholesterol homeostasis and causes the lipid nephrotoxicity in vitro and in vivo, and explored its underlying mechanisms. Inflammatory stress was induced by cytokines (interleukin-1β (IL-1β); tumor necrosis factor α (TNF-α)) to human mesangial cells (HMCs) in vitro and by subcutaneous casein injection in C57BL/6J mice in vivo. The data showed that inflammatory stress exacerbated renal cholesterol ester accumulation in vitro and in vivo. Inflammation increased cellular cholesterol uptake and synthesis via upregulating the expression of low-density lipoprotein receptor (LDLr) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCoA-R), while it decreased cholesterol efflux via downregulating the expression of liver X receptor alpha and ATP-binding cassette transporter A1. The increased lipid accumulation by inflammatory stress induced reactive oxygen species (ROS) and increased levels of endoplasmic reticulum (ER) stress markers (inositol-requiring protein 1 and activating transcription factor 6) in HMCs and kidneys of C57BL/6J mice. This study implied that inflammation promoted renal lipid accumulation and foam cell formation by disrupting cellular cholesterol homeostasis. Increased intracellular lipids under inflammatory stress caused oxidative stress and ER stress in vitro and in vivo which may contribute to renal injury and progression of chronic kidney disease.

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Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (81270493, 81270789, 81200567, 81070631, 81070317, and Key Program, No. 81030008), the Major State Basic Research Development Program of China (973 Program, Nos. 2012CB517700 and 2012CB517500), and the Natural Science Foundation of Chongqing (CSTC,2012jjA10016).

Conflict of Interest

The authors declare they have no competing interests as defined by Molecular Medicine or other interests that might be perceived to influence the results and discussion reported in this paper.

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Authors and Affiliations

  1. Centre for Lipid Research, Key Laboratory of Metabolism on Lipid and Glucose, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China

    Shan Zhong, Lei Zhao, Qing Li, Ping Yang, Yaxi Chen & Xiong Z. Ruan

  2. John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, London, UK

    Zac Varghese, John F. Moorhead & Xiong Z. Ruan

Authors
  1. Shan Zhong
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  2. Lei Zhao
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  3. Qing Li
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  4. Ping Yang
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  5. Zac Varghese
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  6. John F. Moorhead
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  7. Yaxi Chen
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  8. Xiong Z. Ruan
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Correspondence to Yaxi Chen.

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Shan Zhong and Lei Zhao contributed equally to this work.

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Zhong, S., Zhao, L., Li, Q. et al. Inflammatory Stress Exacerbated Mesangial Foam Cell Formation and Renal Injury via Disrupting Cellular Cholesterol Homeostasis. Inflammation 38, 959–971 (2015). https://doi.org/10.1007/s10753-014-0058-0

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