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

• DOI: 10.1038/ncomms10330
• Publication Date: 2016-01-20T11:25:30Z
• Authors: 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
• Keywords: Male; Oncogene Proteins; Science; Q; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Exons; Endoplasmic Reticulum Stress; Immunohistochemistry; Article; Lipocalins; Mice, Mutant Strains; 3. Good health; Mice; Proteinuria; Lipocalin-2; Albumins; Unfolded Protein Response; Animals; Female; Kidney Diseases; WT1 Proteins; Acute-Phase Proteins

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 humans, as novel therapeutic strategy capable counteract the toxic effect of proteinuria. Mechanistically, show that albumin induces tubular unfolded protein response via cytosolic calcium rise, leads apoptosis by Lipocalin 2 (LCN2) modulation through ATF4. Consistent with key role LCN2 CKD progression, Lcn2 gene inactivation decreases ER stress-induced apoptosis, lesions and mortality proteinuric mice. More importantly, inhibition this pathway PBA protects kidneys from morphological functional degradation These are relevant human CKD, is increased patients. conclusion, our study identifies susceptible improve benefit RAS inhibitors proteinuria-induced progression.