A tumor necrosis factor-alpha-mediated pathway promoting autosomal dominant polycystic kidney disease.
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.
Li
Xiaogang
X
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA.
Magenheimer
Brenda S
BS
Xia
Sheng
S
Johnson
Teri
T
Wallace
Darren P
DP
Calvet
James P
JP
Li
Rong
R
D000818:Animals; D018797:Cell Cycle Proteins; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D007249:Inflammation; D007668:Kidney / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D009154:Mutation; D009924:Organ Culture Techniques / Q000379:methods; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000276:immunology*; D050396:TRPP Cation Channels / Q000378:metabolism*; D035582:Transcription Factor TFIIIA / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D018797:Cell Cycle Proteins; D016207:Cytokines; D005136:Eye Proteins; D026901:Membrane Transport Proteins; D050396:TRPP Cation Channels; D035582:Transcription Factor TFIIIA; D014409:Tumor Necrosis Factor-alpha; C409460:OPTN protein, human; C501288:Optn protein, mouse