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

Nat Med. 2008 Aug;14(8):863-8. doi: 10.1038/nm1783. Epub 2008 Jun 15.

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-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins
  • Cell Membrane / metabolism
  • Cytokines / metabolism
  • Eye Proteins / genetics*
  • Eye Proteins / metabolism
  • Genes, Dominant
  • Humans
  • Inflammation
  • Kidney / metabolism
  • Membrane Transport Proteins
  • 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*

Substances

  • Cell Cycle Proteins
  • Cytokines
  • Eye Proteins
  • Membrane Transport Proteins
  • OPTN protein, human
  • Optn protein, mouse
  • TRPP Cation Channels
  • Transcription Factor TFIIIA
  • Tumor Necrosis Factor-alpha
  • polycystic kidney disease 2 protein