title: Stress Response Gene Nupr1 Alleviates Cyclosporin A Nephrotoxicity In Vivo.
abstract: Acute tubular damage is a major cause of renal failure, especially at the early phase of kidney transplant when ischemia-reperfusion injury and cyclosporin A toxicity may coexist. The mechanisms of the latter are largely unknown. Using an mRNA microarray on microdissected tubules from a rat model of cyclosporin A toxicity to describe the related epithelial-specific transcriptional signature in vivo, we found that cyclosporin A induces pathways dependent on the transcription factor ATF4 and identified nuclear protein transcriptional regulator 1 (Nupr1), a stress response gene induced by ATF4, as the gene most strongly upregulated. Upon cyclosporin A treatment, Nupr1-deficient mice exhibited worse renal tubular lesions than wild-type mice. In primary cultures treated with cyclosporin A, renal tubular cells isolated from Nupr1-deficient mice exhibited more apoptosis and ATP depletion than cells from wild-type mice. Furthermore, cyclosporin A decreased protein synthesis and abolished proliferation in wild-type tubular cells, but only reduced proliferation in Nupr1-deficient cells. Compared with controls, mouse models of ischemia-reperfusion injury, urinary obstruction, and hypertension exhibited upregulated expression of renal NUPR1, and cyclosporin A induced Nupr1 expression in cultured human tubular epithelial cells. Finally, immunohistochemical analysis revealed strong expression of NUPR1 in the nuclei of renal proximal tubules of injured human kidney allografts, but not in those of stable allografts. Taken together, these results suggest that epithelial expression of NUPR1 has a protective role in response to injury after renal transplant and, presumably, in other forms of acute tubular damage.
authors.affiliation: Mixed Research Unit 1155, Pierre et Marie Curie University - University Paris 06, Sorbonne Universités, Paris, France; galichon@me.com.|Departments of Renal Intensive Care and Transplantation.|Mixed Research Unit 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Pierre
authors.initials: P
authors.lastname: Galichon
authors.affiliation: Mixed Research Unit 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Bataille
authors.affiliation: Mixed Research Unit 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vandermeersch
authors.affiliation: Mixed Research Unit 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Morgane
authors.initials: M
authors.lastname: Wetzstein
authors.affiliation: Mixed Research Unit 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Xu-Dubois
authors.affiliation: Mixed Research Unit 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: David
authors.initials: D
authors.lastname: Legouis
authors.affiliation: Mixed Research Unit 1155, Pierre et Marie Curie University - University Paris 06, Sorbonne Universités, Paris, France.|Departments of Renal Intensive Care and Transplantation.|Mixed Research Unit 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Hertig
authors.affiliation: Mixed Research Unit 1155, Pierre et Marie Curie University - University Paris 06, Sorbonne Universités, Paris, France.|Mixed Research Unit 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France; and.|Pathology, and.
authors.forename: David
authors.initials: D
authors.lastname: Buob
authors.affiliation: Mixed Research Unit 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Placier
authors.affiliation: Mixed Research Unit 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Naïke
authors.initials: N
authors.lastname: Bigé
authors.affiliation: Biochemistry, Tenon Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lefevre
authors.affiliation: Mixed Research Unit 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Chantal
authors.initials: C
authors.lastname: Jouanneau
authors.affiliation: Mixed Research Unit 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Caroline
authors.initials: C
authors.lastname: Martin
authors.affiliation: Unit 1068, Institut National de la Santé et de la Recherche Médicale, Marseille, France.
authors.forename: Juan Lucio
authors.initials: JL
authors.lastname: Iovanna
authors.affiliation: Mixed Research Unit 1155, Pierre et Marie Curie University - University Paris 06, Sorbonne Universités, Paris, France.|Departments of Renal Intensive Care and Transplantation.|Mixed Research Unit 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Eric
authors.initials: E
authors.lastname: Rondeau
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced* / Q000235:genetics*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics*; D013312:Stress, Physiological
chemical_list: D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C491644:Nupr1 protein, mouse; D016572:Cyclosporine
keywords: Pathophysiology of Renal Disease and Progression; cell activation; cyclosporine nephrotoxicity; gene expression; renal proximal tubule cell