A tumor necrosis factor-α–mediated pathway promoting autosomal dominant polycystic kidney disease
| Autor: | James P. Calvet, Darren P. Wallace, Brenda S. Magenheimer, Teri Johnson, Xiaogang Li, Rong Li, Sheng Xia |
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| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
TRPP Cation Channels medicine.medical_treatment Autosomal dominant polycystic kidney disease Cell Cycle Proteins Biology Kidney urologic and male genital diseases Article General Biochemistry Genetics and Molecular Biology Mice Organ Culture Techniques Germline mutation Transcription Factor TFIIIA Internal medicine medicine Polycystic kidney disease Animals Humans Eye Proteins Genes Dominant Inflammation PKD1 Tumor Necrosis Factor-alpha urogenital system Cilium Cell Membrane Membrane Transport Proteins General Medicine Polycystic Kidney Autosomal Dominant medicine.disease female genital diseases and pregnancy complications Cytokine medicine.anatomical_structure Endocrinology Mutation Cytokines Tumor necrosis factor alpha |
| Zdroj: | Nature Medicine. 14:863-868 |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | Polycystic kidney disease can be caused by germline mutations in the gene encoding PC2 followed by a second somatic 'hit' in the normal allele. Li and her colleagues now show that TNF-α can also act as a second hit and that disease progression can be blocked by anti–TNF-α treatment in an animal model. Autosomal dominant polycystic kidney disease (ADPKD) is caused by heterozygous mutations in either PKD1 or PKD2, genes that encode polycystin-1 and polycystin-2, respectively1. We show here that tumor necrosis factor-α (TNF-α), an inflammatory cytokine present in the cystic fluid of humans with ADPKD, disrupts the localization of polycystin-2 to the plasma membrane and primary cilia through a scaffold protein, FIP2, which is induced by TNF-α. Treatment of mouse embryonic kidney organ cultures with TNF-α resulted in formation of cysts, and this effect was exacerbated in the Pkd2+/− kidneys. TNF-α also stimulated cyst formation in vivo in Pkd2+/− mice. In contrast, treatment of Pkd2+/− mice with the TNF-α inhibitor etanercept prevented cyst formation. These data reveal a pathway connecting TNF-α signaling, polycystins and cystogenesis, the activation of which may reduce functional polycystin-2 below a critical threshold, precipitating the ADPKD cellular phenotype. |
| Databáze: | OpenAIRE |
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