title: Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2.
abstract: In chronic kidney disease (CKD), proteinuria results in severe tubulointerstitial lesions, which ultimately lead to end-stage renal disease. Here we identify 4-phenylbutyric acid (PBA), a chemical chaperone already used in humans, as a novel therapeutic strategy capable to counteract the toxic effect of proteinuria. Mechanistically, we show that albumin induces tubular unfolded protein response via cytosolic calcium rise, which leads to tubular apoptosis by Lipocalin 2 (LCN2) modulation through ATF4. Consistent with the key role of LCN2 in CKD progression, Lcn2 gene inactivation decreases ER stress-induced apoptosis, tubulointerstitial lesions and mortality in proteinuric mice. More importantly, the inhibition of this pathway by PBA protects kidneys from morphological and functional degradation in proteinuric mice. These results are relevant to human CKD, as LCN2 is increased in proteinuric patients. In conclusion, our study identifies a therapeutic strategy susceptible to improve the benefit of RAS inhibitors in proteinuria-induced CKD progression.
authors.affiliation: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.|Service d'Explorations Fonctionnelles, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Khalil
authors.initials: K
authors.lastname: El Karoui
authors.affiliation: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Viau
authors.affiliation: UMR-S 757 INSERM, Université Paris Sud 11, Rue des Adèles, Orsay 91405, France.
authors.forename: Olivier
authors.identifier: http://orcid.org/0000-0003-0377-9163
authors.initials: O
authors.lastname: Dellis
authors.affiliation: INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Institut Cochin, Paris, France.
authors.forename: Alessia
authors.initials: A
authors.lastname: Bagattin
authors.affiliation: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: William
authors.initials: W
authors.lastname: Baron
authors.affiliation: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Burtin
authors.affiliation: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Broueilh
authors.affiliation: INSERM U1163, Université Paris Descartes, Institut Imagine, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Heidet
authors.affiliation: INSERM U1163, Université Paris Descartes, Institut Imagine, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Mollet
authors.affiliation: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Druilhe
authors.affiliation: INSERM U1163, Université Paris Descartes, Institut Imagine, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.affiliation: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Knebelmann
authors.affiliation: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.|Service d'Explorations Fonctionnelles, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Friedlander
authors.affiliation: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.|Service d'Explorations Fonctionnelles, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Bienaimé
authors.affiliation: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Morgan
authors.initials: M
authors.lastname: Gallazzini
authors.affiliation: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Terzi
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000418:Albumins / Q000494:pharmacology; D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005091:Exons / Q000235:genetics; D005260:Female; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011507:Proteinuria / Q000150:complications* / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D000418:Albumins; D047908:Intracellular Signaling Peptides and Proteins; D000071068:Lipocalin-2; D054834:Lipocalins; D008565:Membrane Proteins; C407223:NPHS2 protein; D015513:Oncogene Proteins; D025721:WT1 Proteins; C071332:Lcn2 protein, mouse