title: A Novel Extrinsic Pathway for the Unfolded Protein Response in the Kidney.
abstract: The ribonuclease angiogenin is a component of the mammalian stress response, and functions in both cell-autonomous and non-cell-autonomous ways to promote tissue adaptation to injury. We recently showed that angiogenin regulates tissue homeostasis during AKI associated with endoplasmic reticulum (ER) stress through the production of transfer RNA fragments that interfere with translation initiation and thereby alleviate ER stress. However, whether the paracrine signaling mediated by angiogenin secretion is a genuine component of the ER stress response to kidney injury is unknown. Here, we explored the molecular mechanisms by which angiogenin is secreted upon ER stress, and determined how it modulates the inflammatory microenvironment. In cultured renal epithelial cells, ER stress specifically induced angiogenin secretion under the selective control of inositol-requiring enzyme 1α, a key activator of the unfolded protein response. The transcription factors spliced X-box-binding protein 1 and p65, which are activated by inositol-requiring enzyme 1α upon ER stress, each bound the angiogenin promoter and controlled the amount of angiogenin secreted. Furthermore, p65 promoted angiogenin transcription in an ER stress-dependent manner. Similar to secretion of the ER stress-induced proinflammatory cytokine IL-6, secretion of angiogenin required the ER-Golgi pathway. Notably, incubation of human macrophages with angiogenin promoted macrophage reprogramming toward an activated and proinflammatory phenotype. In patients, angiogenin expression increased upon renal inflammation, and the urinary concentration of angiogenin correlated with the extent of immune-mediated kidney injury. Collectively, our data identify angiogenin as a mediator of the ER stress-dependent inflammatory response and as a potential noninvasive biomarker of AKI.
authors.affiliation: Institut National de la Santé et de le Recherche Médicale (INSERM) U1147, Centre Universitaire des Saints Pères, Paris, France; Université Paris Descartes, Paris, France;
authors.forename: Iadh
authors.initials: I
authors.lastname: Mami
authors.affiliation: Institut National de la Santé et de le Recherche Médicale (INSERM) U1147, Centre Universitaire des Saints Pères, Paris, France; Université Paris Descartes, Paris, France;
authors.forename: Quentin
authors.initials: Q
authors.lastname: Tavernier
authors.affiliation: Service de Néphrologie, Centre Hospitalier Unversitaire de Caen, Caen, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bouvier
authors.affiliation: Institut National de la Santé et de le Recherche Médicale (INSERM) U1147, Centre Universitaire des Saints Pères, Paris, France; Université Paris Descartes, Paris, France;
authors.forename: Rim
authors.initials: R
authors.lastname: Aboukamis
authors.affiliation: Université Paris Descartes, Paris, France; Service de Néphrologie, INSERM U1151, Institut Necker Enfants Malades, Paris, France;
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Desbuissons
authors.affiliation: Université Paris Descartes, Paris, France; Service d'Anatomopathologie, Hôpital Necker, Paris, France;
authors.forename: Marion
authors.initials: M
authors.lastname: Rabant
authors.affiliation: Institut National de la Santé et de le Recherche Médicale (INSERM) U1147, Centre Universitaire des Saints Pères, Paris, France; Université Paris Descartes, Paris, France;
authors.forename: Virginie
authors.initials: V
authors.lastname: Poindessous
authors.affiliation: Institut National de la Santé et de le Recherche Médicale (INSERM) U1147, Centre Universitaire des Saints Pères, Paris, France; Université Paris Descartes, Paris, France; Service de Biochimie, Service de Néphrologie, Hôpital Européen Georges Pompidou, Paris, France;
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: Institut National de la Santé et de le Recherche Médicale (INSERM) U1147, Centre Universitaire des Saints Pères, Paris, France; Université Paris Descartes, Paris, France; Service de Biochimie, Service de Néphrologie, Hôpital Européen Georges Pompidou, Paris, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.affiliation: Paris Cardiovascular Research Center, INSERM, Paris, France; and.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
authors.affiliation: Université Paris Descartes, Paris, France; Service de Néphrologie, Centre Hospitalier Unversitaire de Caen, Caen, France; Service de Néphrologie, Centre Hospitalier Unversitaire de Caen, Caen, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Thervet
authors.affiliation: Oncogenesis Stress Signaling Laboratory, ER440 INSERM, Université de Rennes 1, Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Chevet
authors.affiliation: Université Paris Descartes, Paris, France; Service de Néphrologie, INSERM U1151, Institut Necker Enfants Malades, Paris, France;
authors.forename: Dany
authors.initials: D
authors.lastname: Anglicheau
authors.affiliation: Institut National de la Santé et de le Recherche Médicale (INSERM) U1147, Centre Universitaire des Saints Pères, Paris, France; Université Paris Descartes, Paris, France; Service de Biochimie, Service de Néphrologie, Hôpital Européen Georges Pompidou, Paris, France; npallet@yahoo.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pallet
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D007668:Kidney / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D012259:Ribonuclease, Pancreatic / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: C046366:angiogenin; D012259:Ribonuclease, Pancreatic
keywords: acute rejection; cell activation; cytokines; macrophages; renal tubular epithelial cells
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