Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2

Khalil El Karoui; Amandine Viau; Olivier Dellis; Alessia Bagattin; Clément Nguyen; William Baron; Martine Burtin; Mélanie Broueilh; Laurence Heidet; Géraldine Mollet; Anne Druilhe; Corinne Antignac; Bertrand Knebelmann; Gérard Friedlander; Frank Bienaimé; Morgan Gallazzini; Fabiola Terzi

doi:10.1038/ncomms10330

Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2

Nat Commun. 2016 Jan 20:7:10330. doi: 10.1038/ncomms10330.

Authors

Khalil El Karoui^{1

2}, Amandine Viau¹, Olivier Dellis³, Alessia Bagattin⁴, Clément Nguyen¹, William Baron¹, Martine Burtin¹, Mélanie Broueilh¹, Laurence Heidet⁵, Géraldine Mollet⁵, Anne Druilhe¹, Corinne Antignac⁵, Bertrand Knebelmann¹, Gérard Friedlander^{1

2}, Frank Bienaimé^{1

2}, Morgan Gallazzini¹, Fabiola Terzi¹

Affiliations

¹ 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.
² Service d'Explorations Fonctionnelles, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.
³ UMR-S 757 INSERM, Université Paris Sud 11, Rue des Adèles, Orsay 91405, France.
⁴ INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Institut Cochin, Paris, France.
⁵ INSERM U1163, Université Paris Descartes, Institut Imagine, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute-Phase Proteins / genetics
Acute-Phase Proteins / metabolism*
Albumins / pharmacology
Animals
Endoplasmic Reticulum Stress / drug effects
Endoplasmic Reticulum Stress / genetics
Endoplasmic Reticulum Stress / physiology*
Exons / genetics
Female
Immunohistochemistry
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Kidney Diseases / etiology*
Kidney Diseases / metabolism*
Lipocalin-2
Lipocalins / genetics
Lipocalins / metabolism*
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mice, Mutant Strains
Oncogene Proteins / genetics
Oncogene Proteins / metabolism*
Proteinuria / complications*
Proteinuria / metabolism*
Unfolded Protein Response / drug effects
WT1 Proteins / genetics
WT1 Proteins / metabolism

Substances

Acute-Phase Proteins
Albumins
Intracellular Signaling Peptides and Proteins
Lipocalin-2
Lipocalins
Membrane Proteins
NPHS2 protein
Oncogene Proteins
WT1 Proteins
Lcn2 protein, mouse