PMID- 28667502 OWN - NLM STAT- MEDLINE DCOM- 20180815 LR - 20181113 IS - 1573-2576 (Electronic) IS - 0360-3997 (Linking) VI - 40 IP - 5 DP - 2017 Oct TI - Lysophosphatidic Acid Protects Against Endotoxin-Induced Acute Kidney Injury. PG - 1707-1716 LID - 10.1007/s10753-017-0612-7 [doi] AB - 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, TNFalpha, 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 (TNFalpha 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. FAU - Mirzoyan, Koryun AU - Mirzoyan K AD - U1048, Institut of Cardiovascular and Metabolic Diseases, Institut National de la Sante et de la Recherche Medicale (INSERM), Toulouse, France. AD - Universite Toulouse III Paul-Sabatier Toulouse, Toulouse, France. FAU - Denis, Colette AU - Denis C AD - U1048, Institut of Cardiovascular and Metabolic Diseases, Institut National de la Sante et de la Recherche Medicale (INSERM), Toulouse, France. AD - Universite Toulouse III Paul-Sabatier Toulouse, Toulouse, France. FAU - Casemayou, Audrey AU - Casemayou A AD - U1048, Institut of Cardiovascular and Metabolic Diseases, Institut National de la Sante et de la Recherche Medicale (INSERM), Toulouse, France. AD - Universite Toulouse III Paul-Sabatier Toulouse, Toulouse, France. FAU - Gilet, Marion AU - Gilet M AD - U1048, Institut of Cardiovascular and Metabolic Diseases, Institut National de la Sante et de la Recherche Medicale (INSERM), Toulouse, France. AD - Universite Toulouse III Paul-Sabatier Toulouse, Toulouse, France. FAU - Marsal, Dimitri AU - Marsal D AD - U1048, Institut of Cardiovascular and Metabolic Diseases, Institut National de la Sante et de la Recherche Medicale (INSERM), Toulouse, France. AD - Universite Toulouse III Paul-Sabatier Toulouse, Toulouse, France. FAU - Goudouneche, Dominique AU - Goudouneche D AD - Centre de Microscopie Electronique Appliquee a la Biologie (CMEAB), Faculte de Medecine Rangueil, University of Toulouse, Toulouse, France. FAU - Faguer, Stanislas AU - Faguer S AD - U1048, Institut of Cardiovascular and Metabolic Diseases, Institut National de la Sante et de la Recherche Medicale (INSERM), Toulouse, France. AD - Universite Toulouse III Paul-Sabatier Toulouse, Toulouse, France. FAU - Bascands, Jean-Loup AU - Bascands JL AD - U1188-Universite de La Reunion, Institut National de la Sante et de la Recherche Medicale (INSERM), Toulouse, France. FAU - Schanstra, Joost P AU - Schanstra JP AD - U1048, Institut of Cardiovascular and Metabolic Diseases, Institut National de la Sante et de la Recherche Medicale (INSERM), Toulouse, France. joost-peter.schanstra@inserm.fr. AD - Universite Toulouse III Paul-Sabatier Toulouse, Toulouse, France. joost-peter.schanstra@inserm.fr. FAU - Saulnier-Blache, Jean-Sebastien AU - Saulnier-Blache JS AUID- ORCID: 0000-0002-8971-7723 AD - U1048, Institut of Cardiovascular and Metabolic Diseases, Institut National de la Sante et de la Recherche Medicale (INSERM), Toulouse, France. jean-sebastien.saulnier-blache@inserm.fr. AD - Universite Toulouse III Paul-Sabatier Toulouse, Toulouse, France. jean-sebastien.saulnier-blache@inserm.fr. LA - eng PT - Journal Article PL - United States TA - Inflammation JT - Inflammation JID - 7600105 RN - 0 (Cytokines) RN - 0 (Endotoxins) RN - 0 (Lipopolysaccharides) RN - 0 (Lysophospholipids) RN - 0 (Protective Agents) RN - AYI8EX34EU (Creatinine) RN - PG6M3969SG (lysophosphatidic acid) SB - IM MH - Acute Kidney Injury/chemically induced/*prevention & control MH - Animals MH - Blood Urea Nitrogen MH - Creatinine/blood MH - Cytokines/drug effects/metabolism MH - Endotoxins MH - Inflammation/prevention & control MH - Lipopolysaccharides MH - Lysophospholipids/*pharmacology MH - Mice MH - Mice, Inbred C57BL MH - Protective Agents MH - RAW 264.7 Cells OTO - NOTNLM OT - endotoxemia OT - kidney OT - lysophosphatidic acid OT - macrophages EDAT- 2017/07/02 06:00 MHDA- 2018/08/16 06:00 CRDT- 2017/07/02 06:00 PHST- 2017/07/02 06:00 [pubmed] PHST- 2018/08/16 06:00 [medline] PHST- 2017/07/02 06:00 [entrez] AID - 10.1007/s10753-017-0612-7 [pii] AID - 10.1007/s10753-017-0612-7 [doi] PST - ppublish SO - Inflammation. 2017 Oct;40(5):1707-1716. doi: 10.1007/s10753-017-0612-7.