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

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, 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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Figure 1: Effects of TNF-α on FIP2 and polycystin-2 in IMCD cells.
Figure 2: TNF-α triggers cyst formation in cultured embryonic kidneys and is present in human ADPKD cyst fluid.
Figure 3: The TNF-α inhibitor etanercept prevents cyst formation in Pkd2+/− mice.

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Acknowledgements

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.

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X.L. performed most experiments. B.S.M. assisted in organ culture experiments. D.P.W. handled human materials and human primary cell culture. S.X. assisted in experimental analysis. T.J. provided all histology analysis. J.P.C. developed organ culture assay. R.L. supervised the whole project.

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Correspondence to Rong Li.

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Competing interests

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–6 and Supplementary Methods (PDF 1062 kb)

Supplementary Movie 1

PC2 and α-tubulin staining at 0 h of TNF-α treatment. (WMV 708 kb)

Supplementary Movie 2

PC2 and α-tubulin staining at 16 h of TNF-α treatment. (WMV 645 kb)

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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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