title: Dual role of MUC1 mucin in kidney ischemia-reperfusion injury: Nephroprotector in early phase, but pro-fibrotic in late phase.
abstract: Acute kidney injury (AKI) is characterized by acute tubular necrosis (ATN) which involves mainly proximal tubules. Past AKI is associated with higher risk of chronic kidney disease (CKD). The MUC1 mucin is a large glycoprotein responsible for epithelial protection and locates to convoluted distal tubules and collecting ducts. Since MUC1 activates the epithelial-mesenchymal transition (EMT) in carcinoma cells, we hypothesized that MUC1 could be involved in epithelial tubular cell plasticity, a process that not only accompanies epithelial repair, but also participates into kidney fibrosis, histological substratum of CKD. In cultured human proximal cells and in human kidney allograft biopsies, we observed MUC1 induction in proximal tubules displaying ATN. Transient MUC1 induction localized with mesenchymal and stem-cell markers and was associated in vitro with reduced anoikis. In a mouse ischemia-reperfusion (IR) model, Muc1 expression mitigates severe tubular injury, as WT displayed less ATN than Muc1 KO mice. But, WT mice displayed more severe kidney fibrosis than Muc1 KO 28days after ischemia. Besides, sustained Muc1 expression in WT was associated with less kidney M2 macrophages. Human kidney biopsies performed within the first week (W1) of transplantation in the context of IR showed MUC1 W1 induction associated with EMT markers. Protocol biopsies performed 3months after demonstrated sustained abnormal MUC1 induction in atrophic tubules within kidney fibrosis. Altogether these data showed that sustained abnormal MUC1 induction accompanies failing epithelial repair, chronic inflammation and kidney fibrosis. In conclusion, MUC1 exerts opposite effects during kidney response to IR: first protective and then harmful.
authors.affiliation: Univ. Lille, UMR-S 1172, JPARC, Jean-Pierre Aubert Research Center, F-59000 Lille, France; Inserm, UMR-S 1172, Team "Mucins, Epithelial Differentiation and Carcinogenesis", F-59000 Lille, France; CHU Lille, Pathology Institute, Centre de Biologie Pathologie, Rue Oscar Lambret, F-59037 Lille, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Gibier
authors.affiliation: Univ. Lille, UMR-S 1172, JPARC, Jean-Pierre Aubert Research Center, F-59000 Lille, France; Inserm, UMR-S 1172, Team "Mucins, Epithelial Differentiation and Carcinogenesis", F-59000 Lille, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Hémon
authors.affiliation: Univ. Lille, UMR-S 1172, JPARC, Jean-Pierre Aubert Research Center, F-59000 Lille, France; Inserm, UMR-S 1172, Team "Mucins, Epithelial Differentiation and Carcinogenesis", F-59000 Lille, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Fanchon
authors.affiliation: Univ. Lille, UMR-S 1172, JPARC, Jean-Pierre Aubert Research Center, F-59000 Lille, France; Inserm, UMR-S 1172, Team "Mucins, Epithelial Differentiation and Carcinogenesis", F-59000 Lille, France.
authors.forename: Kelly
authors.initials: K
authors.lastname: Gaudelot
authors.affiliation: Univ. Lille, EA4483, F-59000 Lille, France; EA4483, Faculté de Médecine, Pôle Recherche, Place de Verdun, F-59000 Lille, France; CHU Lille, Department of Biochemistry and Molecular Biology, Centre de Biologie Pathologie, Rue Oscar Lambret, F-59037 Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pottier
authors.affiliation: Univ. Lille, UMR-S 1172, JPARC, Jean-Pierre Aubert Research Center, F-59000 Lille, France; Inserm, UMR-S 1172, Team "Mucins, Epithelial Differentiation and Carcinogenesis", F-59000 Lille, France.
authors.forename: Bélinda
authors.initials: B
authors.lastname: Ringot
authors.affiliation: Univ. Lille, UMR-S 1172, JPARC, Jean-Pierre Aubert Research Center, F-59000 Lille, France; Inserm, UMR-S 1172, Team "Mucins, Epithelial Differentiation and Carcinogenesis", F-59000 Lille, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Seuningen
authors.affiliation: Univ. Lille, EA4483, F-59000 Lille, France; EA4483, Faculté de Médecine, Pôle Recherche, Place de Verdun, F-59000 Lille, France; CHU Lille, Department of Nephrology, Hôpital Huriez, Rue Michel Polonovski, F-59037 Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Glowacki
authors.affiliation: Univ. Lille, EA4483, F-59000 Lille, France; EA4483, Faculté de Médecine, Pôle Recherche, Place de Verdun, F-59000 Lille, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Cauffiez
authors.affiliation: Univ. Lille, UMR-S 1172, JPARC, Jean-Pierre Aubert Research Center, F-59000 Lille, France; Inserm, UMR-S 1172, Team "Alzheimer & Tauopathies", F-59000 Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Blum
authors.affiliation: CHU Lille, Pathology Institute, Centre de Biologie Pathologie, Rue Oscar Lambret, F-59037 Lille, France; Univ. Lille, CNRS UMR 8161, SIRIC ONCOLille, F-59000 Lille, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Copin
authors.affiliation: Univ. Lille, UMR-S 1172, JPARC, Jean-Pierre Aubert Research Center, F-59000 Lille, France; Inserm, UMR-S 1172, Team "Mucins, Epithelial Differentiation and Carcinogenesis", F-59000 Lille, France.
authors.forename: Michaël
authors.initials: M
authors.lastname: Perrais
authors.affiliation: Univ. Lille, UMR-S 1172, JPARC, Jean-Pierre Aubert Research Center, F-59000 Lille, France; Inserm, UMR-S 1172, Team "Mucins, Epithelial Differentiation and Carcinogenesis", F-59000 Lille, France; CHU Lille, Pathology Institute, Centre de Biologie Pathologie, Rue Oscar Lambret, F-59037 Lille, France. Electronic address: viviane.gnemmi@chru-lille.fr.
authors.forename: Viviane
authors.initials: V
authors.lastname: Gnemmi
mesh_terms: D000818:Animals; D005355:Fibrosis; D057809:HEK293 Cells; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C060192:MUC1 protein, human; D018396:Mucin-1; C577056:muc1 protein, mouse
keywords: Acute kidney injury; Epithelial-mesenchymal transition; Fibrosis; Ischemia-reperfusion; MUC1