title: Transforming growth factor-beta induces renal epithelial jagged-1 expression in fibrotic disease.
abstract: For elucidation of the mechanisms by which growth factors and cytokines affect renal epithelial cells, gene array analysis of renal cells cultured in the presence of transforming growth factor-beta1 (TGF-beta1) was performed. Many genes that were not previously considered to be involved in renal cell biologic processes were affected, one of which was jagged-1. The jagged ligand/notch receptor family controls the formation of boundaries between groups of cells and regulates cell fates. On the basis of the array analysis, jagged-1 expression was further evaluated in cultured cells and in C57BL/6 mice with a model of unilateral ureteral obstruction (UUO). Recombinant human TGF-beta1 increased jagged-1 mRNA levels at concentrations between 10(-11) and 10(-10) M. There was a commensurate increase in jagged-1 protein levels, as assessed by Western blotting. The expression of jagged-1 mRNA and protein was observed to be significantly increased in the kidneys of C57BL/6 mice with obstructed ureters, compared with the contralateral kidneys, at 7 and 14 d of UUO. Immunohistochemical analyses demonstrated jagged-1 expression in distal tubules of kidneys from normal mice or contralateral kidneys from mice with UUO. Jagged-1 protein expression was increased in tubules not yet in apparent atrophy in the kidneys with an obstructed ureter. Jagged-1 expression was significantly increased in the kidneys of normal mice treated with TGF-beta1 and was decreased in the kidneys of mice with UUO treated with a TGF-beta receptor II-Fc chimera. These results suggest that jagged-1 is expressed in normal kidneys and that this expression is upregulated during renal disease, in a TGF-beta-dependent manner.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri 63110-1092, USA. morrisse@im.wustl.edu
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Morrissey
authors.forename: Guangjie
authors.initials: G
authors.lastname: Guo
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Moridaira
authors.forename: Melanie
authors.initials: M
authors.lastname: Fitzgerald
authors.forename: Ruth
authors.initials: R
authors.lastname: McCracken
authors.forename: Timothy
authors.initials: T
authors.lastname: Tolley
authors.forename: Saulo
authors.initials: S
authors.lastname: Klahr
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D000072099:Serrate-Jagged Proteins; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011506:Proteins; D012333:RNA, Messenger; D000072099:Serrate-Jagged Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1