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Polycystins and renovascular mechanosensory transduction

Nature Reviews Nephrology volume 6, pages 530–538 (2010)Cite this article

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Abstract

Autosomal dominant polycystic kidney disease is a common disorder, affecting approximately one in 1,000 individuals. This disease is characterized by the presence of renal and extrarenal cysts, as well as by cardiovascular abnormalities, including hypertension and intracranial aneurysms. Mutations in the PKD1 gene account for 85% of cases, whereas mutations in PKD2 account for the remaining 15% of cases. Findings from the past 10 years indicate that polycystins, the products of the PKD genes, have a key role in renal and vascular mechanosensory transduction. In the primary cilium of renal, nodal, and endothelial cells, polycystins are proposed to act as flow sensors. In addition, the ratio of polycystin-1 to polycystin-2 regulates pressure sensing in arterial myocytes. In this Review, we summarize the data indicating that polycystins are key molecules in mechanotransduction. Moreover, we discuss the role of nucleotide release and autocrine and/or paracrine purinergic signaling in both fluid flow and pressure responses. Finally, we discuss the possible role of altered mechanosensory transduction in the etiology of polycystic kidney disease.

Key Points

  • The polycystin receptor–ion channel complex formed by polycystin-1 and polycystin-2 is localized in the primary cilium and is necessary for flow sensing in both renal epithelial and endothelial cells

  • Bending of the primary cilium by fluid flow is anticipated to induce a conformational change in the polycystins, which results in calcium influx

  • Fluid flow induces the cilium-dependent release of nucleotides and the autocrine and/or paracrine stimulation of purinergic receptors; pressure induces the cilium-independent release of ATP

  • Activation of the endothelial primary cilium polycystin complex by fluid flow mediates nitric oxide release, causing vasodilation

  • Polycystin-2 in nodal sensory cilia is involved in determination of left–right asymmetry

  • The ratio of polycystin-1 to polycystin-2 regulates the opening of stretch-activated ion channels in arterial myocytes and affects myogenic tone

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Figure 1: Membrane topology of the receptor-ion channel complex polycystin-1/polycystin-2.
Figure 2: Role of the primary cilium in fluid flow sensing.
Figure 3: Role of polycystins in left–right asymmetry.
Figure 4: Hemodynamic forces that act on blood vessels.
Figure 5: Role of ATP and purinergic stimulation in the flow response.
Figure 6: Role of polycystins in the regulation of stretch-activated ion channels.

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References

  1. Delmas, P. Polycystins: from mechanosensation to gene regulation. Cell 118, 145–148 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Zhou, J. Polycystins and primary cilia: primers for cell cycle progression. Annu. Rev. Physiol. 71, 83–113 (2009).

    Article  CAS  Google Scholar 

  4. Harris, P. C. & Torres, V. E. Polycystic kidney disease. Annu. Rev. Med. 60, 321–337 (2009).

    Article  CAS  Google Scholar 

  5. Delmas, P. Polycystins: polymodal receptor/ion-channel cellular sensors. Pflugers Arch. 451, 264–276 (2005).

    Article  CAS  Google Scholar 

  6. Voets, T. & Nilius, B. TRPs make sense. J. Membr. Biol. 192, 1–8 (2003).

    Article  CAS  Google Scholar 

  7. Clapham, D. E. TRP channels as cellular sensors. Nature 426, 517–524 (2003).

    Article  CAS  Google Scholar 

  8. Nauli, S. M. & Zhou, J. Polycystins and mechanosensation in renal and nodal cilia. Bioessays 26, 844–856 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Nauli, S. M. et al. Endothelial cilia are fluid shear sensors that regulate calcium signaling and nitric oxide production through polycystin-1. Circulation 117, 1161–1171 (2008).

    Article  CAS  Google Scholar 

  11. Aboualaiwi, W. A. et al. Ciliary polycystin-2 is a mechanosensitive calcium channel involved in nitric oxide signaling cascades. Circ. Res. 104, 860–869 (2009).

    Article  CAS  Google Scholar 

  12. McGrath, J., Somlo, S., Makova, S., Tian, X. & Brueckner, M. Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114, 61–73 (2003).

    Article  CAS  Google Scholar 

  13. Pennekamp, P. et al. The ion channel polycystin-2 is required for left-right axis determination in mice. Curr. Biol. 12, 938–943 (2002).

    Article  CAS  Google Scholar 

  14. Sharif Naeini, R. et al. Polycystin-1 and -2 dosage regulates pressure sensing. Cell 139, 587–596 (2009).

    Article  CAS  Google Scholar 

  15. Fliegauf, M., Benzing, T. & Omran, H. When cilia go bad: cilia defects and ciliopathies. Nat. Rev. Mol. Cell Biol. 8, 880–893 (2007).

    Article  CAS  Google Scholar 

  16. Hildebrandt, F. & Otto, E. Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease? Nat. Rev. Genet. 6, 928–940 (2005).

    Article  CAS  Google Scholar 

  17. Badano, J. L., Mitsuma, N., Beales, P. L. & Katsanis, N. The ciliopathies: An emerging class of human genetic disorders. Annu. Rev. Genomics Hum. Genet. 7, 125–148 (2006).

    Article  CAS  Google Scholar 

  18. Praetorius, H. A. & Spring, K. R. Bending the MDCK cell primary cilium increases intracellular calcium. J. Membr. Biol. 184, 71–79 (2001).

    Article  CAS  Google Scholar 

  19. Praetorius, H. A. & Spring, K. R. A physiological view of the primary cilium. Annu. Rev. Physiol. 67, 515–529 (2005).

    Article  CAS  Google Scholar 

  20. Praetorius, H. A. & Spring, K. R. Removal of the MDCK cell primary cilium abolishes flow sensing. J. Membr. Biol. 191, 69–76 (2003).

    Article  CAS  Google Scholar 

  21. Forman, J. R., Qamar, S., Paci, E., Sandford, R. N. & Clarke, J. The remarkable mechanical strength of polycystin-1 supports a direct role in mechanotransduction. J. Mol. Biol. 349, 861–871 (2005).

    Article  CAS  Google Scholar 

  22. Qian, F., Wei, W., Germino, G. & Oberhauser, A. The nanomechanics of polycystin-1 extracellular region. J. Biol. Chem. 280, 40723–40730 (2005).

    Article  CAS  Google Scholar 

  23. Kottgen, M. et al. TRPP2 and TRPV4 form a polymodal sensory channel complex. J. Cell Biol. 182, 437–447 (2008).

    Article  Google Scholar 

  24. Tsiokas, L. et al. Specific association of the gene product of PKD2 with the TRPC1 channel. Proc. Natl Acad. Sci. USA 96, 3934–3939 (1999).

    Article  CAS  Google Scholar 

  25. Maroto, R. et al. TRPC1 forms the stretch-activated cation channel in vertebrate cells. Nat. Cell Biol. 7, 179–185 (2005).

    Article  CAS  Google Scholar 

  26. Gottlieb, P. et al. Revisiting TRPC1 and TRPC6 mechanosensitivity. Pflugers Arch. 455, 529–540 (2007).

    Google Scholar 

  27. Rohatgi, R. et al. Mechanoregulation of intracellular Ca2+ in human autosomal recessive polycystic kidney disease cyst-lining renal epithelial cells. Am. J. Physiol. Renal Physiol. 294, F890–F899 (2008).

    Article  CAS  Google Scholar 

  28. Fischer, E. et al. Defective planar cell polarity in polycystic kidney disease. Nat. Genet. 38, 21–23 (2006).

    Article  CAS  Google Scholar 

  29. Jonassen, J. A., San Agustin, J., Follit, J. A. & Pazour, G. J. Deletion of IFT20 in the mouse kidney causes misorientation of the mitotic spindle and cystic kidney disease. J. Cell Biol. 183, 377–384 (2008).

    Article  CAS  Google Scholar 

  30. Wu, G. et al. Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nat. Genet. 24, 75–78 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. Lu, W. et al. Perinatal lethality with kidney and pancreas defects in mice with a targetted Pkd1 mutation. Nat. Genet. 17, 179–181 (1997).

    Article  CAS  Google Scholar 

  33. Boulter, C. et al. Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene. Proc. Natl Acad. Sci. USA 98, 12174–12179 (2001).

    Article  CAS  Google Scholar 

  34. Piontek, K., Menezes, L. F., Garcia-Gonzalez, M. A., Huso, D. L. & Germino, G. G. A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat. Med. 13, 1490–1495 (2007).

    Article  CAS  Google Scholar 

  35. Davenport, J. R. et al. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr. Biol. 17, 1586–1594 (2007).

    Article  CAS  Google Scholar 

  36. Karcher, C. et al. Lack of a laterality phenotype in Pkd1 knock-out embryos correlates with absence of polycystin-1 in nodal cilia. Differentiation 73, 425–432 (2005).

    Article  CAS  Google Scholar 

  37. Vogel, P. et al. Situs inversus in Dpcd/Poll−/−, Nme7−/−, and Pkd1l1−/− mice. Vet. Pathol. 47, 120–131 (2010).

    Article  CAS  Google Scholar 

  38. Bichet, D., Peters, D., Patel, A., Delmas, P. & Honoré, E. The cardiovascular polycystins: insights from autosomal dominant polycystic kidney disease and transgenic animal models. Trends Cardiovasc. Med. 16, 292–298 (2006).

    Article  CAS  Google Scholar 

  39. Ecder, T. & Schrier, R. W. Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease. Nat. Rev. Nephrol. 5, 221–228 (2009).

    Article  CAS  Google Scholar 

  40. Torres, V. E. et al. Vascular expression of polycystin-2. J. Am. Soc. Nephrol. 12, 1–9 (2001).

    CAS  PubMed  Google Scholar 

  41. Griffin, M. D., Torres, V. E., Grande, J. P. & Kumar, R. Vascular expression of polycystin. J. Am. Soc. Nephrol. 8, 616–626 (1997).

    CAS  PubMed  Google Scholar 

  42. Qian, Q. et al. Analysis of the polycystins in aortic vascular smooth muscle cells. J. Am. Soc. Nephrol. 14, 2280–2287 (2003).

    Article  CAS  Google Scholar 

  43. Persu, A. et al. Modifier effect of ENOS in autosomal dominant polycystic kidney disease. Hum. Mol. Genet. 11, 229–241 (2002).

    Article  CAS  Google Scholar 

  44. Hahn, C. & Schwartz, M. A. Mechanotransduction in vascular physiology and atherogenesis. Nat. Rev. Mol. Cell. Biol. 10, 53–62 (2009).

    Article  CAS  Google Scholar 

  45. Morel, N. et al. PKD1 haploinsufficiency is associated with altered vascular reactivity and abnormal calcium signaling in the mouse aorta. Pflugers Arch. 457, 845–856 (2008).

    Article  Google Scholar 

  46. 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).

    Article  CAS  Google Scholar 

  47. Koulen, P. et al. Polycystin-2 is an intracellular calcium release channel. Nat. Cell Biol. 4, 191–197 (2002).

    Article  CAS  Google Scholar 

  48. Praetorius, H. A. & Leipziger, J. Released nucleotides amplify the cilium-dependent, flow-induced [Ca2+]i response in MDCK cells. Acta Physiol. (Oxford) 197, 241–251 (2009).

    Article  CAS  Google Scholar 

  49. Hovater, M. B. et al. Loss of apical monocilia on collecting duct principal cells impairs ATP secretion across the apical cell surface and ATP-dependent and flow-induced calcium signals. Purinergic Signal. 4, 155–170 (2008).

    Article  CAS  Google Scholar 

  50. Xu, C. et al. Attenuated, flow-induced ATP release contributes to absence of flow-sensitive, purinergic Cai2+ signaling in human ADPKD cyst epithelial cells. Am. J. Physiol. Renal Physiol. 296, F1464–F1476 (2009).

    Article  CAS  Google Scholar 

  51. Praetorius, H. A. & Leipziger, J. Fluid flow sensing and triggered nucleotide release in epithelia. J. Physiol. 586, 2669 (2008).

    Article  CAS  Google Scholar 

  52. Leipziger, J. Control of epithelial transport via luminal P2 receptors. Am. J. Physiol. Renal Physiol. 284, F419–F432 (2003).

    Article  CAS  Google Scholar 

  53. Vallon, V. P2 receptors in the regulation of renal transport mechanisms. Am. J. Physiol. Renal Physiol. 294, F10–F27 (2008).

    Article  CAS  Google Scholar 

  54. Burnstock, G. Physiology and pathophysiology of purinergic neurotransmission. Physiol. Rev. 87, 659–797 (2007).

    Article  CAS  Google Scholar 

  55. Yamamoto, K. et al. Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice. Nat. Med. 12, 133–137 (2006).

    Article  CAS  Google Scholar 

  56. Praetorius, H. A., Frokiaer, J. & Leipziger, J. Transepithelial pressure pulses induce nucleotide release in polarized MDCK cells. Am. J. Physiol. Renal Physiol. 288, 133–141 (2009).

    Article  Google Scholar 

  57. Derezic, D. & Cecuk, L. Hydrostatic pressure within renal cysts. Br. J. Urol. 54, 93–94 (1982).

    Article  CAS  Google Scholar 

  58. Tanner, G. A., McQuillan, P. F., Maxwell, M. R., Keck, J. K. & McAteer, J. A. An in vitro test of the cell stretch-proliferation hypothesis of renal cyst enlargement. J. Am. Soc. Nephrol. 6, 1230–1241 (1995).

    CAS  PubMed  Google Scholar 

  59. 59. Lantinga- van Leeuwen, I. S. et al. Kidney-specific inactivation of the Pkd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice. Hum. Mol. Genet. 16, 3188–3196 (2007).

    Article  Google Scholar 

  60. Fetterman, G. H., Ravitch, M. M. & Sherman, F. E. Cystic changes in fetal kidneys following ureteral ligation: studies by microdissection. Kidney Int. 5, 111–121 (1974).

    Article  CAS  Google Scholar 

  61. Quinlan, M. R., Docherty, N. G., Watson, R. W. & Fitzpatrick, J. M. Exploring mechanisms involved in renal tubular sensing of mechanical stretch following ureteric obstruction. Am. J. Physiol. Renal Physiol. 295, F1–F11 (2008).

    Article  CAS  Google Scholar 

  62. Jensen, M. E., Odgaard, E., Christensen, M. H., Praetorius, H. A. & Leipziger, J. Flow-induced [Ca2+]i increase depends on nucleotide release and subsequent purinergic signaling in the intact nephron. J. Am. Soc. Nephrol. 18, 2062–2070 (2007).

    Article  CAS  Google Scholar 

  63. Wilson, P. D., Hovater, J. S., Casey, C. C., Fortenberry, J. A. & Schwiebert, E. M. ATP release mechanisms in primary cultures of epithelia derived from the cysts of polycystic kidneys. J. Am. Soc. Nephrol. 10, 218–229 (1999).

    CAS  PubMed  Google Scholar 

  64. Schwiebert, E. M. et al. Autocrine extracellular purinergic signaling in epithelial cells derived from polycystic kidneys. Am. J. Physiol. Renal Physiol. 282, F763–F775 (2002).

    Article  CAS  Google Scholar 

  65. Hovater, M. B., Olteanu, D., Welty, E. A. & Schwiebert, E. M. Purinergic signaling in the lumen of a normal nephron and in remodeled PKD encapsulated cysts. Purinergic Signal. 4, 109–124 (2008).

    Article  CAS  Google Scholar 

  66. Olteanu, D., Hovater, M. B. & Schwiebert, E. M. Intraluminal autocrine purinergic signaling within cysts: implications for the progression of diseases that involve encapsulated cyst formation. Am. J. Physiol. Renal Physiol. 292, F11–F14 (2007).

    Article  CAS  Google Scholar 

  67. Brayden, J. E., Earley, S., Nelson, M. T. & Reading, S. Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow. Clin. Exp. Pharmacol. Physiol. 35, 1116–1120 (2008).

    Article  CAS  Google Scholar 

  68. Hill, M. A., Davis, M. J., Meininger, G. A., Potocnik, S. J. & Murphy, T. V. Arteriolar myogenic signalling mechanisms: Implications for local vascular function. Clin. Hemorheol. Microcirc. 34, 67–79 (2006).

    PubMed  Google Scholar 

  69. Stossel, T. P. et al. Filamins as integrators of cell mechanics and signalling. Nat. Rev. Mol. Cell Biol. 2, 138–145 (2001).

    Article  CAS  Google Scholar 

  70. Mochizuki, T. et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272, 1339–1342 (1996).

    Article  CAS  Google Scholar 

  71. Chen, X. Z. et al. Transport function of the naturally occurring pathogenic polycystin-2 mutant, R742X. Biochem. Biophys. Res. Commun. 282, 1251–1256 (2001).

    Article  CAS  Google Scholar 

  72. Praetorius, H. A. & Leipziger, J. ATP release from non-excitable cells. Purinergic Signal. 5, 433–446 (2009).

    Article  CAS  Google Scholar 

  73. Kobori, T., Smith, G. D., Sandford, R. & Edwardson, J. M. The transient receptor potential channels TRPP2 and TRPC1 form a heterotetramer with a 2:2 stoichiometry and an alternating subunit arrangement. J. Biol. Chem. 284, 35507–35513 (2009).

    Article  CAS  Google Scholar 

  74. Yu, Y. et al. Structural and molecular basis of the assembly of the TRPP2/PKD1 complex. Proc. Natl Acad. Sci. USA 106, 11558–11563 (2009).

    Article  CAS  Google Scholar 

  75. Bodin, P. & Burnstock, G. Purinergic signalling: ATP release. Neurochem. Res. 26, 959–969 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to the ANR 2005 cardiovasculaire-obésité-diabète, to the ANR 2008 du gène à la physiopathologie, to the Association for information and research on genetic kidney disease France, to the Fondation del Duca, to the Fondation de la recherche médicale, to the Fondation de France, to the Fondation de recherche sur l'hypertension artérielle, to the Fédération pour la recherche sur le cerveau, to Société Générale AM, to the Université de Nice-Sophia Antipolis and to the CNRS for financial support. We are grateful to Dr Sophie Demolombe, Institute of Molecular and Cellular Pharmacology, CNRS, Valbonne Sophia Antipolis, France, for critical reading of the manuscript.

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  1. Institut de Pharmacologie Moléculaire et Cellulaire, UMR CNRS 6097, Université de Nice-Sophia Antipolis, Valbonne, 06560, France

    Amanda Patel & Eric Honoré

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A. Patel and E. Honoré contributed equally to researching data for the article, discussing content, writing, and reviewing/editing the manuscript before submission.

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Patel, A., Honoré, E. Polycystins and renovascular mechanosensory transduction. Nat Rev Nephrol 6, 530–538 (2010). https://doi.org/10.1038/nrneph.2010.97

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