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

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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.

References

  1. 1

    Wilson, P.D. Polycystic kidney disease. N. Engl. J. Med. 350, 151–164 (2004).

  2. 2

    Qian, F., Watnick, T.J., Onuchic, L.F. & Germino, G.G. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell 87, 979–987 (1996).

  3. 3

    Lantinga-van Leeuwen, I.S. et al. Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. Hum. Mol. Genet. 13, 3069–3077 (2004).

  4. 4

    Martinez, J.R. & Grantham, J.J. Polycystic kidney disease: etiology, pathogenesis and treatment. Dis. Mon. 41, 693–765 (1995).

  5. 5

    Pfeffer, K. Biological functions of tumor necrosis factor cytokines and their receptors. Cytokine Growth Factor Rev. 14, 185–191 (2003).

  6. 6

    Todorov, V., Muller, M., Schweda, F. & Kurtz, A. Tumor necrosis factor-α inhibits renin gene expression. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283, R1046–R1051 (2002).

  7. 7

    Vielhauer, V. & Mayadas, T.N. Functions of TNF and its receptors in renal disease: distinct roles in inflammatory tissue injury and immune regulation. Semin. Nephrol. 27, 286–308 (2007).

  8. 8

    Peters, D.J. & Breuning, M.H. Autosomal dominant polycystic kidney disease: modification of disease progression. Lancet 358, 1439–1444 (2001).

  9. 9

    Nakamura, T. et al. Increased endothelin and endothelin receptor mRNA expression in polycystic kidneys of cpk mice. J. Am. Soc. Nephrol. 4, 1064–1072 (1993).

  10. 10

    Gardner, K.D. Jr ., Burnside, J.S., Elzinga, L.W. & Locksley, R.M. Cytokines in fluids from polycystic kidneys. Kidney Int. 39, 718–724 (1991).

  11. 11

    Li, Y., Kang, J. & Horwitz, M.S. Interaction of an adenovirus E3 14.7-kilodalton protein with a novel tumor necrosis factor-α–inducible cellular protein containing leucine zipper domains. Mol. Cell. Biol. 18, 1601–1610 (1998).

  12. 12

    Hattula, K. & Peranen, J. FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis. Curr. Biol. 10, 1603–1606 (2000).

  13. 13

    Sahlender, D.A. et al. Optineurin links myosin VI to the Golgi complex and is involved in Golgi organization and exocytosis. J. Cell Biol. 169, 285–295 (2005).

  14. 14

    Nauli, S.M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33, 129–137 (2003).

  15. 15

    Cai, Y. et al. Identification and characterization of polycystin-2, the PKD2 gene product. J. Biol. Chem. 274, 28557–28565 (1999).

  16. 16

    Geng, L. et al. Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif. J. Cell Sci. 119, 1383–1395 (2006).

  17. 17

    Igarashi, P. & Somlo, S. Genetics and pathogenesis of polycystic kidney disease. J. Am. Soc. Nephrol. 13, 2384–2398 (2002).

  18. 18

    Vandorpe, D.H. et al. The cytoplasmic C-terminal fragment of polycystin-1 regulates a Ca2+-permeable cation channel. J. Biol. Chem. 276, 4093–4101 (2001).

  19. 19

    Magenheimer, B.S. et al. Early embryonic renal tubules of wild-type and polycystic kidney disease kidneys respond to cAMP stimulation with cystic fibrosis transmembrane conductance regulator/Na+,K+,2Cl Co-transporter–dependent cystic dilation. J. Am. Soc. Nephrol. 17, 3424–3437 (2006).

  20. 20

    Aderka, D., Engelmann, H., Maor, Y., Brakebusch, C. & Wallach, D. Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J. Exp. Med. 175, 323–329 (1992).

  21. 21

    De Groote, D., Grau, G.E., Dehart, I. & Franchimont, P. Stabilisation of functional tumor necrosis factor-α by its soluble TNF receptors. Eur. Cytokine Netw. 4, 359–362 (1993).

  22. 22

    Wu, G. et al. Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 93, 177–188 (1998).

  23. 23

    Mann, D.L. et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109, 1594–1602 (2004).

  24. 24

    Dell, K.M. et al. A novel inhibitor of tumor necrosis factor-α converting enzyme ameliorates polycystic kidney disease. Kidney Int. 60, 1240–1248 (2001).

  25. 25

    Ferrell, J.E. Jr. Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. Curr. Opin. Cell Biol. 14, 140–148 (2002).

  26. 26

    Lee, D.F. et al. IKKβ suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130, 440–455 (2007).

  27. 27

    Shillingford, J.M. et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc. Natl. Acad. Sci. USA 103, 5466–5471 (2006).

  28. 28

    Li, X. et al. Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nat. Cell Biol. 7, 1202–1212 (2005).

  29. 29

    Fisher, R.A. On the interpretation of χ2 from contingency tables and the calculation of P. J. R. Stat. Soc. [Ser. A] 85, 87–94 (1922).

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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.

Author information

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.

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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