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.
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We thank S. Somlo (Yale Medical School) for providing the Pkd2+/− mice and YCC2 antibody; J. Zhou (Harvard Medical School) for the 96525 and 96521 antibodies; T. Nichols, B. Slaughter, N. Pavelka, P. Suraneni, G. Reif and J.-P. Rey for technical assistance; and J. Grantham and R. Krumlauf for helpful discussion. This work was supported by funds from the Stowers Institute for Medical Research to R.L., a Polycystic Kidney Disease Center grant from the US National Institutes of Health (P50 DK05301-07) to J.P.C. and D.P.W. and a Polycystic Kidney Disease Foundation grant to X.L.
X.L. and R.L. have patent applications, including U.S. patent applications, which are directed to (among other things) the use of TNF-α inhibitors to treat polycystic kidney disease and other related diseases.
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Li, X., Magenheimer, B., Xia, S. et al. A tumor necrosis factor-α–mediated pathway promoting autosomal dominant polycystic kidney disease. Nat Med 14, 863–868 (2008). https://doi.org/10.1038/nm1783
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