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 and Fabiola Terzi ()
Additional contact information
Khalil El Karoui: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151—CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Hôpital Necker Enfants Malades
Amandine Viau: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151—CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Hôpital Necker Enfants Malades
Olivier Dellis: UMR-S 757 INSERM, Université Paris Sud 11, Rue des Adèles
Alessia Bagattin: INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Institut Cochin
Clément Nguyen: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151—CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Hôpital Necker Enfants Malades
William Baron: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151—CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Hôpital Necker Enfants Malades
Martine Burtin: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151—CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Hôpital Necker Enfants Malades
Mélanie Broueilh: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151—CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Hôpital Necker Enfants Malades
Laurence Heidet: INSERM U1163, Université Paris Descartes, Institut Imagine, Hôpital Necker Enfants Malades
Géraldine Mollet: INSERM U1163, Université Paris Descartes, Institut Imagine, Hôpital Necker Enfants Malades
Anne Druilhe: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151—CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Hôpital Necker Enfants Malades
Corinne Antignac: INSERM U1163, Université Paris Descartes, Institut Imagine, Hôpital Necker Enfants Malades
Bertrand Knebelmann: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151—CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Hôpital Necker Enfants Malades
Gérard Friedlander: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151—CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Hôpital Necker Enfants Malades
Frank Bienaimé: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151—CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Hôpital Necker Enfants Malades
Morgan Gallazzini: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151—CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Hôpital Necker Enfants Malades
Fabiola Terzi: Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151—CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Hôpital Necker Enfants Malades

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10330

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