Transforming growth factor-β induces renal epithelial jagged-1 expression in fibrotic disease

• Published in: Journal of the American Society of Nephrology 2002-06, Vol.13 (6), p.1499-1508
• Main Authors: MORRISSEY, Jeremiah, GUO, Guangjie, MORIDAIRA, Kazuaki, FITZGERALD, Melanie, MCCRACKEN, Ruth, TOLLEY, Timothy, KLAHR, Saulo
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Calcium-Binding Proteins; Cells, Cultured; Dose-Response Relationship, Drug; Epithelium - drug effects; Epithelium - metabolism; Fibrosis; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidneys; Medical sciences; Membrane Proteins; Mice; Mice, Inbred C57BL; Nephrology. Urinary tract diseases; Oligonucleotide Array Sequence Analysis; Proteins - genetics; RNA, Messenger - analysis; Serrate-Jagged Proteins; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta1; Urinary system involvement in other diseases. Miscellaneous
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1097/01.ASN.0000017905.77985.4A

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.