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Suppression of chronic damage in renal allografts by liver X receptor (LXR) activation: relevant contribution of macrophage LXRα

Liver X receptors (LXR)-α,β regulate intracellular cholesterol homeostasis and inhibit inflammatory gene expression. We studied the effects of the LXRα,β-agonist GW3965 on acute and chronic organ damage in the F344-LEW rat kidney transplantation model. In addition, to gain LXR isoform and cell-speci...

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Main Authors: Kiss, Eva (Author) , Popovic, Zoran V. (Author) , Bedke, Jens (Author) , Wang, Shijun (Author) , Bonrouhi, Mahnaz (Author) , Gretz, Norbert (Author) , Stettner, Paula (Author) , Teupser, Daniel (Author) , Thiery, Joachim (Author) , Porubský, Štefan (Author) , Adams, Judith (Author) , Gröne, Hermann-Josef (Author)
Format: Article (Journal)
Language:English
Published: 5 May 2011
In: The American journal of pathology
Year: 2011, Volume: 179, Issue: 1, Pages: 92-103
ISSN:1525-2191
DOI:10.1016/j.ajpath.2011.03.019
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ajpath.2011.03.019
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S000294401100335X
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Author Notes:Eva Kiss, Zoran Popovic, Jens Bedke, Shijun Wang, Mahnaz Bonrouhi, Norbert Gretz, Paula Stettner, Daniel Teupser, Joachim Thiery, Stefan Porubsky, Judith Adams, and Hermann-Josef Gröne
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Summary:Liver X receptors (LXR)-α,β regulate intracellular cholesterol homeostasis and inhibit inflammatory gene expression. We studied the effects of the LXRα,β-agonist GW3965 on acute and chronic organ damage in the F344-LEW rat kidney transplantation model. In addition, to gain LXR isoform and cell-specific insights BALB/c kidneys were transplanted into mice with macrophage overexpression of LXRα (mLXRα-tg) and evaluated 7 and 42 days after transplantation. After 56 days GW3965 improved significantly function and morphology of rat kidney allografts by substantial reduction of mononuclear cell infiltrate and fibrosis; in vitro GW3965 reduced inflammatory activity of bone marrow-derived macrophages (BMDMs) and alloreactivity of T cells. Kidneys transplanted into mLXRα-tg mice were also protected from development of chronic allograft dysfunction. Similarly to GW3965-activated BMDMs, mLXRα-tg macrophages secreted significantly less monocyte chemoattractant protein 1 and macrophage inflammatory protein 1β. Interestingly, 7 days after transplantation, when the total number of intragraft macrophages did not differ, evidently more arginase 1- and mannose receptor C type 1-positive cells were found in LXR rat and mice kidney allografts; in vitro both LXR activation by GW3965 and mLXRα overexpression accentuated the induction of alternative activation of BMDMs by IL-4/IL-13, suggesting an additional mechanism by LXRs to prevent graft damage. The results highlight the relevance of macrophage LXRα in allograft rejection and prevention of fibrosis.
Item Description:Gesehen am 04.08.2022
Physical Description:Online Resource
ISSN:1525-2191
DOI:10.1016/j.ajpath.2011.03.019

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