title: Increased urinary lysophosphatidic acid in mouse with subtotal nephrectomy: potential involvement in chronic kidney disease.
abstract: Increased incidence of chronic kidney disease (CKD) with consecutive progression to end-stage renal disease represents a significant burden to healthcare systems. Renal tubulointerstitial fibrosis (TIF) is a classical hallmark of CKD and is well correlated with the loss of renal function. The bioactive lysophospholipid lysophosphatidic acid (LPA), acting through specific G-protein-coupled receptors, was previously shown to be involved in TIF development in a mouse model of unilateral ureteral obstruction. Here, we study the role of LPA in a mouse subjected to subtotal nephrectomy (SNx), a more chronic and progressive model of CKD. Five months after surgical nephron reduction, SNx mice showed massive albuminuria, extensive TIF, and glomerular hypertrophy when compared to sham-operated animals. Urinary and plasma levels of LPA were analyzed using liquid chromatography tandem mass spectrometry. LPA was significantly increased in SNx urine, not in plasma, and was significantly correlated with albuminuria and TIF. Moreover, SNx mice showed significant downregulation in the renal expression of lipid phosphate phosphohydrolases (LPP1, 2, and 3) that might be involved in reduced LPA bioavailability through dephosphorylation. We concluded that SNx increases urinary LPA through a mechanism that could involve co-excretion of plasma LPA with albumin associated with a reduction of its catabolism in the kidney. Because of the previously demonstrated profibrotic activity of LPA, the association of urinary LPA with TIF suggests the potential involvement of LPA in the development of advanced CKD in the SNx mouse model. Targeting LPA metabolism might represent an interesting approach in CKD treatment.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France.
authors.forename: Koryun
authors.initials: K
authors.lastname: Mirzoyan
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Baïotto
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France.|Lipidomic Core Facility, Metatoul Platform, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Dupuy
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Marsal
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France.
authors.forename: Colette
authors.initials: C
authors.lastname: Denis
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Vinel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sicard
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France.|Lipidomic Core Facility, Metatoul Platform, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Bertrand-Michel
authors.affiliation: DéTROI - Inserm U1188 - Université de La Réunion, Sainte Clotilde, France.
authors.forename: Jean-Loup
authors.initials: JL
authors.lastname: Bascands
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France.
authors.forename: Joost P
authors.initials: JP
authors.lastname: Schanstra
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.|Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Klein
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France. jean-sebastien.saulnier-blache@inserm.fr.|Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France. jean-sebastien.saulnier-blache@inserm.fr.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Saulnier-Blache
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000652:urine*; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008246:Lysophospholipids / Q000097:blood / Q000652:urine*; D051379:Mice; D009392:Nephrectomy; D009395:Nephritis, Interstitial / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000652:urine*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000652:urine*
chemical_list: C431577:Ltap protein, mouse; D008246:Lysophospholipids; D009419:Nerve Tissue Proteins; D010711:Phosphatidate Phosphatase; C479566:Plpp3 protein, mouse; C032881:lysophosphatidic acid
keywords: Chronic kidney disease; Liquid chromatography tandem mass spectrometry; Lysophosphatidic acid; Urine