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Li, X, Magenheimer, BS, Xia, S, Johnson, T, Wallace, DP, Calvet, JP and Li, R (2008) A tumor necrosis factor-alpha-mediated pathway promoting autosomal dominant polycystic kidney disease. Nat. Med. 14:863-8
Autosomal dominant polycystic kidney disease (ADPKD) is caused by heterozygous mutations in either PKD1 or PKD2, genes that encode polycystin-1 and polycystin-2, respectively. We show here that tumor necrosis factor-alpha (TNF-alpha), 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-alpha. Treatment of mouse embryonic kidney organ cultures with TNF-alpha resulted in formation of cysts, and this effect was exacerbated in the Pkd2(+/-) kidneys. TNF-alpha also stimulated cyst formation in vivo in Pkd2(+/-) mice. In contrast, treatment of Pkd2(+/-) mice with the TNF-alpha inhibitor etanercept prevented cyst formation. These data reveal a pathway connecting TNF-alpha signaling, polycystins and cystogenesis, the activation of which may reduce functional polycystin-2 below a critical threshold, precipitating the ADPKD cellular phenotype.
Animals; Cell Membrane/metabolism; Cytokines/metabolism; Eye Proteins/genetics; Eye Proteins/metabolism; Genes, Dominant; Humans; Inflammation; Kidney/metabolism; Mice; Mutation; Organ Culture Techniques/methods; Polycystic Kidney, Autosomal Dominant/genetics; Polycystic Kidney, Autosomal Dominant/immunology; TRPP Cation Channels/metabolism; Transcription Factor TFIIIA/genetics; Transcription Factor TFIIIA/metabolism; Tumor Necrosis Factor-alpha/metabolism
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