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Lysophosphatidic Acid Protects Against Endotoxin-Induced Acute Kidney Injury

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Abstract

Septic shock is the most common cause of acute kidney injury (AKI), but the underlying mechanisms remain unclear and no targeted therapies exist. Lysophosphatidic acid (LPA) is a bioactive lipid which in vivo administration was reported to mitigate inflammation and injuries caused by bacterial endotoxemia in the liver and lung. The objective of the present study was to determine whether LPA can protect against sepsis-associated AKI. C57BL/6 mice were treated with LPA 18:1 (5 mg/kg, i.p.) 1 h before being injected with the endotoxin lipopolysaccharide (LPS), and AKI was evaluated after 24 h. LPA significantly decreased the elevation of plasma urea and creatinine caused by LPS. In the kidney, LPA pretreatment significantly reduced the upregulation of inflammatory cytokines (IL-6, TNFα, monocyte chemoattractant protein-1 (MCP-1)), and completely prevented downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and upregulation of heme oxygenase-1 caused by LPS. LPA also prevented LPS-mediated alterations of the renal mitochondrial ultrastructure. In vitro pretreatment with LPA 18:1 significantly attenuated LPS-induced upregulation of the inflammatory cytokines (TNFα and MCP-1) in RAW264 macrophages. Moreover, in vivo LPS treatment lowered urinary LPA concentration and reduced LPA anabolic enzymes (autotaxin and acylglycerol kinase), and increased the LPA catalytic enzyme (lipid phosphate phosphatase 2) expression in the kidney cortex. In conclusion, exogenous LPA exerted a protective action against renal inflammation and injuries caused by bacterial endotoxemia. Moreover, LPS reduces the renal production of LPA suggesting that sepsis-associated AKI could be mediated, at least in part, by alleviation of the protective action of endogenous LPA.

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Acknowledgments

This work was supported by grants from INSERM. Koryun Mirzoyan is supported by a Ph.D. grant from Europe (ERASMUS MUNDUS, MEDEA). Justine Bertrand-Michel and Aude Dupuy from the Toulouse’s Lipidomic Core Facility (www.metatoul.fr) are gratefully acknowledged for carrying out LC-MS/MS quantification of the LPA in urine and plasma. We also thank Alexandre Lucas from the Protein Cellular Analysis facility (www.i2mc.inserm.fr/index.php/en/technical-facilities/protein-cellular-analysis-pca) for the quantification of cytokines. All authors participated in the conception and design or analysis and interpretation of the data, contributed to drafting and revising the manuscript, and gave final approval of the version to be published.

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Authors and Affiliations

  1. U1048, Institut of Cardiovascular and Metabolic Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France

    Koryun Mirzoyan, Colette Denis, Audrey Casemayou, Marion Gilet, Dimitri Marsal, Stanislas Faguer, Joost P. Schanstra & Jean-Sébastien Saulnier-Blache

  2. Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France

    Koryun Mirzoyan, Colette Denis, Audrey Casemayou, Marion Gilet, Dimitri Marsal, Stanislas Faguer, Joost P. Schanstra & Jean-Sébastien Saulnier-Blache

  3. Centre de Microscopie Electronique Appliquée à la Biologie (CMEAB), Faculté de Médecine Rangueil, University of Toulouse, Toulouse, France

    Dominique Goudounéche

  4. U1188—Université de La Réunion, Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France

    Jean-Loup Bascands

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  1. Koryun Mirzoyan
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Correspondence to Joost P. Schanstra or Jean-Sébastien Saulnier-Blache.

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Mirzoyan, K., Denis, C., Casemayou, A. et al. Lysophosphatidic Acid Protects Against Endotoxin-Induced Acute Kidney Injury. Inflammation 40, 1707–1716 (2017). https://doi.org/10.1007/s10753-017-0612-7

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