A tumor necrosis factor-α-mediated pathway promoting autosomal dominant polycystic kidney disease

Xiaogang Li, Brenda S. Magenheimer, Sheng Xia, Teri Johnson, Darren P. Wallace, James P. Calvet, Rong Li

Research output: Contribution to journalArticle

Abstract

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-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.

Original languageEnglish (US)
Pages (from-to)863-868
Number of pages6
JournalNature Medicine
Volume14
Issue number8
DOIs
StatePublished - Aug 2008
Externally publishedYes

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Autosomal Dominant Polycystic Kidney
Tumor Necrosis Factor-alpha
Cysts
TRPP Cation Channels
Kidney
Cilia
Organ Culture Techniques
Cell membranes
Scaffolds
Genes
Chemical activation
Cell Membrane
Cytokines
Phenotype
Mutation
Fluids
polycystic kidney disease 2 protein
Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Li, X., Magenheimer, B. S., Xia, S., Johnson, T., Wallace, D. P., Calvet, J. P., & Li, R. (2008). A tumor necrosis factor-α-mediated pathway promoting autosomal dominant polycystic kidney disease. Nature Medicine, 14(8), 863-868. https://doi.org/10.1038/nm1783

A tumor necrosis factor-α-mediated pathway promoting autosomal dominant polycystic kidney disease. / Li, Xiaogang; Magenheimer, Brenda S.; Xia, Sheng; Johnson, Teri; Wallace, Darren P.; Calvet, James P.; Li, Rong.

In: Nature Medicine, Vol. 14, No. 8, 08.2008, p. 863-868.

Research output: Contribution to journalArticle

Li, X, Magenheimer, BS, Xia, S, Johnson, T, Wallace, DP, Calvet, JP & Li, R 2008, 'A tumor necrosis factor-α-mediated pathway promoting autosomal dominant polycystic kidney disease', Nature Medicine, vol. 14, no. 8, pp. 863-868. https://doi.org/10.1038/nm1783
Li X, Magenheimer BS, Xia S, Johnson T, Wallace DP, Calvet JP et al. A tumor necrosis factor-α-mediated pathway promoting autosomal dominant polycystic kidney disease. Nature Medicine. 2008 Aug;14(8):863-868. https://doi.org/10.1038/nm1783
Li, Xiaogang ; Magenheimer, Brenda S. ; Xia, Sheng ; Johnson, Teri ; Wallace, Darren P. ; Calvet, James P. ; Li, Rong. / A tumor necrosis factor-α-mediated pathway promoting autosomal dominant polycystic kidney disease. In: Nature Medicine. 2008 ; Vol. 14, No. 8. pp. 863-868.
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