title: Transforming growth factor alpha (TGF-alpha) and other targets of tumor necrosis factor-alpha converting enzyme (TACE) in murine polycystic kidney disease.
abstract: Transforming growth factor-alpha (TGF-alpha) is abnormally expressed in autosomal recessive polycystic kidney disease (ARPKD). Tumor necrosis factor-alpha converting enzyme (TACE), a metalloproteinase, mediates TGF-alpha processing. In this study, we sought to determine whether TGF-alpha was an absolute requirement for renal cystogenesis and whether its absence would modulate disease severity or related growth factors/receptors expression. Bpk heterozygotes were bred with TGF-alpha null mice to produce cystic and noncystic offspring with or without TGF-alpha. Assessments included kidney weight (KW), body weight (BW), blood urea nitrogen (BUN), and kidney and liver immunohistology. Western analysis assessed kidney expression of amphiregulin (AR), epidermal growth factor (EGF), heparin-binding EGF (HB-EGF), and their receptors, EGFR and ErbB4. A PCR-based methodology for genotyping bpk mice was also developed. No significant differences in KW, BW, KW/BW%, or BUN were seen in cystic mice with versus without TGF-alpha. Cystic kidney disease and liver disease histology were similar. AR, EGF, HB-EGF, EGFR, and ErbB4 were abnormally expressed to an equal degree in kidneys of mice with versus without TGF-alpha. Although previous data suggest a critical role of TGF-alpha in murine PKD, these data show that TGF-alpha is not required for renal cyst formation or kidney or liver disease progression. We speculate that the therapeutic effect of WTACE2 could have been due to effects on several TACE targets, including TGF-alpha, AR, and ErbB4, as well as metalloproteinases other than TACE.
authors.affiliation: Rainbow Center for Childhood PKD, Department of Pediatrics, Rainbow Babies and Children's Hospital and Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Raghad
authors.initials: R
authors.lastname: Nemo
authors.forename: Noel
authors.initials: N
authors.lastname: Murcia
authors.forename: Katherine Macrae
authors.initials: KM
authors.lastname: Dell
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000483:Alleles; D066258:Amphiregulin; D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight; D018450:Disease Progression; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000096:biosynthesis; D066246:ErbB Receptors / Q000096:biosynthesis; D005808:Genes, Recessive; D005838:Genotype; D006023:Glycoproteins / Q000096:biosynthesis; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007668:Kidney / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D052177:Kidney Diseases, Cystic / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009929:Organ Size; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000201:enzymology* / Q000235:genetics; D016133:Polymerase Chain Reaction; D066247:Receptor, ErbB-4; D016211:Transforming Growth Factor alpha / Q000378:metabolism*
chemical_list: D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D006023:Glycoproteins; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse