Pflügers Archiv - European Journal of Physiology

, Volume 468, Issue 9, pp 1595–1607 | Cite as

TRPV4 is associated with central rather than nephrogenic osmoregulation

  • Sylvie Janas
  • François Seghers
  • Olivier Schakman
  • Mohammad Alsady
  • Peter Deen
  • Joris Vriens
  • Fadel Tissir
  • Bernd Nilius
  • Johannes Loffing
  • Philippe Gailly
  • Olivier DevuystEmail author
Organ physiology


TRPV4 is a polymodal cation channel expressed in osmosensitive neurons of the hypothalamus and in the mammalian nephron. The segmental distribution and role(s) of TRPV4 in osmoregulation remain debated. We investigated the renal distribution pattern of TRPV4 and the functional consequences of its disruption in mouse models. Using qPCR on microdissected segments, immunohistochemistry, and a LacZ reporter mouse, we found that TRPV4 is abundantly expressed in the proximal tubule, the late distal convoluted tubule, and throughout the connecting tubule and collecting duct, including principal and intercalated cells. TRPV4 was undetectable in the glomeruli and thick ascending limb and weakly abundant in the early distal convoluted tubule. Metabolic studies in Trpv4 +/+ and Trpv4 −/− littermates revealed that the lack of TRPV4 did not influence activity, food and water intake, renal function, and urinary concentration at baseline. The mice showed a similar response to furosemide, water loading and deprivation, acid loading, and dietary NaCl restriction. However, Trpv4 −/− mice showed a significantly lower vasopressin synthesis and release after water deprivation, with a loss of the positive correlation between plasma osmolality and plasma vasopressin levels, and a delayed water intake upon acute administration of hypertonic saline. Specific activation of TRPV4 in primary cultures of proximal tubule cells increased albumin uptake, whereas no effect of TRPV4 deletion could be observed at baseline. These data reveal that, despite its abundant expression in tubular segments, TRPV4 does not play a major role in the kidney or is efficiently compensated when deleted. Instead, TRPV4 is critical for the release of vasopressin, the sensation of thirst, and the central osmoregulation.


Osmoregulation TRPV4 Tubular functions Vasopressin Thirst 



These studies were supported by the Belgian agencies ‘Fonds National de la Recherche Scientifique’ (FNRS), ‘Fonds de la Recherche Scientifique Médicale’ (FRSM), and ‘Association belge contre les maladies neuro-musculaires’ (ABMM), the concerted Research Action (10/15-029), the Interuniversity Poles of Attraction Belgian Science Policy (P7/13), the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 305608 (EURenOmics), the “Association française contre les myopathies” (AFM grant 16738), the Swiss National Science Foundation project grant 310030_146490; the KFSP RADIZ (Rare Disease Initiative Zurich), and MINZ (Molecular Imaging Network Zurich) from the University of Zurich. We are grateful to Drs. M. A. Knepper (Bethesda) and C. A. Wagner (Zurich) for help and advice and to H. Debaix, Y. Cnops, S. Druart, N. Amraoui, and X. Yerna for excellent technical assistance. F. Seghers is a Research Fellow of the FNRS.

Compliance with ethical standards

Conflict of interest

The authors declare that that they have no conflicts of interest.

Research involving animals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

424_2016_1850_MOESM1_ESM.docx (941 kb)
Supplementary Material 1 Below is the link to the electronic supplementary material. (DOCX 940 kb)


  1. 1.
    Ahrabi AK, Terryn S, Valenti G, Caron N, Serradeil-Le Gal C, Raufaste D, Nielsen S, Horie S, Verbavatz JM, Devuyst O (2007) PKD1 haploinsufficiency causes a syndrome of inappropriate antidiuresis in mice. J Am Soc Nephrol 18:1740–1753. doi: 10.1681/ASN.2006010052 CrossRefPubMedGoogle Scholar
  2. 2.
    Berrout J, Jin M, Mamenko M, Zaika O, Pochynyuk O, O’Neil RG (2012) Function of transient receptor potential cation channel subfamily V member 4 (TRPV4) as a mechanical transducer in flow-sensitive segments of renal collecting duct system. J Biol Chem 287:8782–8791. doi: 10.1074/jbc.M111.308411 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Berrout J, Mamenko M, Zaika OL, Chen L, Zang W, Pochynyuk O, O’Neil RG (2014) Emerging role of the calcium-activated, small conductance, SK3 K+ channel in distal tubule function: regulation by TRPV4. PLoS One 9:e95149. doi: 10.1371/journal.pone.0095149 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bouley R, Breton S, Sun T, McLaughlin M, Nsumu NN, Lin HY, Ausiello DA, Brown D (2000) Nitric oxide and atrial natriuretic factor stimulate cGMP-dependent membrane insertion of aquaporin 2 in renal epithelial cells. J Clin Invest 106:1115–1126. doi: 10.1172/JCI9594 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bouley R, Hasler U, Lu HA, Nunes P, Brown D (2008) Bypassing vasopressin receptor signaling pathways in nephrogenic diabetes insipidus. Semin Nephrol 28:266–278. doi: 10.1016/j.semnephrol.2008.03.010 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bouley R, Pastor-Soler N, Cohen O, McLaughlin M, Breton S, Brown D (2005) Stimulation of AQP2 membrane insertion in renal epithelial cells in vitro and in vivo by the cGMP phosphodiesterase inhibitor sildenafil citrate (Viagra). Am J Physiol Renal Physiol 288:F1103–F1112. doi: 10.1152/ajprenal.00337.2004 CrossRefPubMedGoogle Scholar
  7. 7.
    Bourque CW (2008) Central mechanisms of osmosensation and systemic osmoregulation. Nat Rev Neurosci 9:519–531. doi: 10.1038/nrn2400 CrossRefPubMedGoogle Scholar
  8. 8.
    Bourque CW, Ciura S, Trudel E, Stachniak TJ, Sharif-Naeini R (2007) Neurophysiological characterization of mammalian osmosensitive neurones. Exp Physiol 92:499–505. doi: 10.1113/expphysiol.2006.035634 CrossRefPubMedGoogle Scholar
  9. 9.
    Bourque CW, Oliet SH, Richard D (1994) Osmoreceptors, osmoreception, and osmoregulation. Front Neuroendocrinol 15:231–274. doi: 10.1006/frne.1994.1010 CrossRefPubMedGoogle Scholar
  10. 10.
    Buggy J, Jonhson AK (1977) Preoptic-hypothalamic periventricular lesions: thirst deficits and hypernatremia. Am J Physiol 233:R44–R52PubMedGoogle Scholar
  11. 11.
    Carreno FR, Ji LL, Cunningham JT (2009) Altered central TRPV4 expression and lipid raft association related to inappropriate vasopressin secretion in cirrhotic rats. Am J Physiol Regul Integr Comp Physiol 296:R454–R466. doi: 10.1152/ajpregu.90460.2008 CrossRefPubMedGoogle Scholar
  12. 12.
    Ciura S, Liedtke W, Bourque CW (2011) Hypertonicity sensing in organum vasculosum lamina terminalis neurons: a mechanical process involving TRPV1 but not TRPV4. J Neurosci 31:14669–14676. doi: 10.1523/JNEUROSCI.1420-11.2011 CrossRefPubMedGoogle Scholar
  13. 13.
    Feetham CH, Nunn N, Barrett-Jolley R (2015) The depressor response to intracerebroventricular hypotonic saline is sensitive to TRPV4 antagonist RN1734. Front Pharmacol 6:83. doi: 10.3389/fphar.2015.00083 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Feetham CH, Nunn N, Lewis R, Dart C, Barrett-Jolley R (2015) TRPV4 and K(Ca) ion channels functionally couple as osmosensors in the paraventricular nucleus. Br J Pharmacol 172:1753–1768. doi: 10.1111/bph.13023 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Gu Y, Gu C (2014) Physiological and pathological functions of mechanosensitive ion channels. Mol Neurobiol 50:339–347. doi: 10.1007/s12035-014-8654-4 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Jouret F, Auzanneau C, Debaix H, Wada GH, Pretto C, Marbaix E, Karet FE, Courtoy PJ, Devuyst O (2005) Ubiquitous and kidney-specific subunits of vacuolar H+-ATPase are differentially expressed during nephrogenesis. J Am Soc Nephrol 16:3235–3246. doi: 10.1681/ASN.2004110935 CrossRefPubMedGoogle Scholar
  17. 17.
    Kinsman B, Cowles J, Lay J, Simmonds SS, Browning KN, Stocker SD (2014) Osmoregulatory thirst in mice lacking the transient receptor potential vanilloid type 1 (TRPV1) and/or type 4 (TRPV4) receptor. Am J Physiol Regul Integr Comp Physiol 307:R1092–R1100. doi: 10.1152/ajpregu.00102.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kunert-Keil C, Bisping F, Kruger J, Brinkmeier H (2006) Tissue-specific expression of TRP channel genes in the mouse and its variation in three different mouse strains. BMC Genomics 7:159. doi: 10.1186/1471-2164-7-159 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Lechner SG, Markworth S, Poole K, Smith ES, Lapatsina L, Frahm S, May M, Pischke S, Suzuki M, Ibanez-Tallon I, Luft FC, Jordan J, Lewin GR (2011) The molecular and cellular identity of peripheral osmoreceptors. Neuron 69:332–344. doi: 10.1016/j.neuron.2010.12.028 CrossRefPubMedGoogle Scholar
  20. 20.
    Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, Heller S (2000) Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103:525–535CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Liedtke W, Friedman JM (2003) Abnormal osmotic regulation in trpv4 −/− mice. Proc Natl Acad Sci U S A 100:13698–13703. doi: 10.1073/pnas.1735416100 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Liedtke W, Tobin DM, Bargmann CI, Friedman JM (2003) Mammalian TRPV4 (VR-OAC) directs behavioral responses to osmotic and mechanical stimuli in Caenorhabditis elegans. Proc Natl Acad Sci U S A 100(Suppl 2):14531–14536. doi: 10.1073/pnas.2235619100 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Mamenko M, Zaika O, Boukelmoune N, O’Neil RG, Pochynyuk O (2014) Deciphering physiological role of the mechanosensitive TRPV4 channel in the distal nephron. Am J Physiol Renal Physiol:ajprenal 00485:02014. doi: 10.1152/ajprenal.00485.2014 Google Scholar
  24. 24.
    Mizuno A, Matsumoto N, Imai M, Suzuki M (2003) Impaired osmotic sensation in mice lacking TRPV4. Am J Physiol Cell Physiol 285:C96–C101. doi: 10.1152/ajpcell.00559.2002 CrossRefPubMedGoogle Scholar
  25. 25.
    Morishita T, Tsutsui M, Shimokawa H, Sabanai K, Tasaki H, Suda O, Nakata S, Tanimoto A, Wang KY, Ueta Y, Sasaguri Y, Nakashima Y, Yanagihara N (2005) Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms. Proc Natl Acad Sci U S A 102:10616–10621. doi: 10.1073/pnas.0502236102 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Nilius B, Honore E (2012) Sensing pressure with ion channels. Trends Neurosci 35:477–486. doi: 10.1016/j.tins.2012.04.002 CrossRefPubMedGoogle Scholar
  27. 27.
    Nilius B, Vriens J, Prenen J, Droogmans G, Voets T (2004) TRPV4 calcium entry channel: a paradigm for gating diversity. Am J Physiol Cell Physiol 286:C195–C205. doi: 10.1152/ajpcell.00365.2003 CrossRefPubMedGoogle Scholar
  28. 28.
    Oliet SH, Bourque CW (1992) Properties of supraoptic magnocellular neurones isolated from the adult rat. J Physiol 455:291–306CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Oliet SH, Bourque CW (1993) Mechanosensitive channels transduce osmosensitivity in supraoptic neurons. Nature 364:341–343. doi: 10.1038/364341a0 CrossRefPubMedGoogle Scholar
  30. 30.
    Pearce D, Soundararajan R, Trimpert C, Kashlan OB, Deen PM, Kohan DE (2015) Collecting duct principal cell transport processes and their regulation. Clin J Am Soc Nephrol 10:135–146. doi: 10.2215/CJN.05760513 CrossRefPubMedGoogle Scholar
  31. 31.
    Pernot E, Terryn S, Cheong SC, Markadieu N, Janas S, Blockmans M, Jacoby M, Pouillon V, Gayral S, Rossier BC, Beauwens R, Erneux C, Devuyst O, Schurmans S (2011) The inositol Inpp5k 5-phosphatase affects osmoregulation through the vasopressin-aquaporin 2 pathway in the collecting system. Pflugers Arch 462:871–883. doi: 10.1007/s00424-011-1028-0 CrossRefPubMedGoogle Scholar
  32. 32.
    Pochynyuk O, Zaika O, O’Neil RG, Mamenko M (2013) Novel insights into TRPV4 function in the kidney. Pflugers Arch 465:177–186. doi: 10.1007/s00424-012-1190-z CrossRefPubMedGoogle Scholar
  33. 33.
    Raghavan V, Rbaibi Y, Pastor-Soler NM, Carattino MD, Weisz OA (2014) Shear stress-dependent regulation of apical endocytosis in renal proximal tubule cells mediated by primary cilia. Proc Natl Acad Sci U S A 111:8506–8511. doi: 10.1073/pnas.1402195111 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Raghavan V, Weisz OA (2016) Discerning the role of mechanosensors in regulating proximal tubule function. Am J Physiol Renal Physiol 310:F1–F5. doi: 10.1152/ajprenal.00373.2015 CrossRefPubMedGoogle Scholar
  35. 35.
    Sharif Naeini R, Witty MF, Seguela P, Bourque CW (2006) An N-terminal variant of Trpv1 channel is required for osmosensory transduction. Nat Neurosci 9:93–98. doi: 10.1038/nn1614 CrossRefPubMedGoogle Scholar
  36. 36.
    Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD (2000) OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat Cell Biol 2:695–702. doi: 10.1038/35036318 CrossRefPubMedGoogle Scholar
  37. 37.
    Taniguchi J, Tsuruoka S, Mizuno A, Sato J, Fujimura A, Suzuki M (2007) TRPV4 as a flow sensor in flow-dependent K+ secretion from the cortical collecting duct. Am J Physiol Renal Physiol 292:F667–F673. doi: 10.1152/ajprenal.00458.2005 CrossRefPubMedGoogle Scholar
  38. 38.
    Terryn S, Jouret F, Vandenabeele F, Smolders I, Moreels M, Devuyst O, Steels P, Van Kerkhove E (2007) A primary culture of mouse proximal tubular cells, established on collagen-coated membranes. Am J Physiol Renal Physiol 293:F476–F485. doi: 10.1152/ajprenal.00363.2006 CrossRefPubMedGoogle Scholar
  39. 39.
    Tian W, Fu Y, Garcia-Elias A, Fernandez-Fernandez JM, Vicente R, Kramer PL, Klein RF, Hitzemann R, Orwoll ES, Wilmot B, McWeeney S, Valverde MA, Cohen DM (2009) A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia. Proc Natl Acad Sci U S A 106:14034–14039. doi: 10.1073/pnas.0904084106 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Tian W, Salanova M, Xu H, Lindsley JN, Oyama TT, Anderson S, Bachmann S, Cohen DM (2004) Renal expression of osmotically responsive cation channel TRPV4 is restricted to water-impermeant nephron segments. Am J Physiol Renal Physiol 287:F17–F24. doi: 10.1152/ajprenal.00397.2003 CrossRefPubMedGoogle Scholar
  41. 41.
    Tsushima H, Mori M (2006) Antidipsogenic effects of a TRPV4 agonist, 4alpha-phorbol 12,13-didecanoate, injected into the cerebroventricle. Am J Physiol Regul Integr Comp Physiol 290:R1736–R1741. doi: 10.1152/ajpregu.00043.2005 CrossRefPubMedGoogle Scholar
  42. 42.
    Vriens J, Watanabe H, Janssens A, Droogmans G, Voets T, Nilius B (2004) Cell swelling, heat, and chemical agonists use distinct pathways for the activation of the cation channel TRPV4. Proc Natl Acad Sci U S A 101:396–401. doi: 10.1073/pnas.0303329101 CrossRefPubMedGoogle Scholar
  43. 43.
    Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, Nilius B (2003) Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424:434–438. doi: 10.1038/nature01807 CrossRefPubMedGoogle Scholar
  44. 44.
    Wu L, Gao X, Brown RC, Heller S, O’Neil RG (2007) Dual role of the TRPV4 channel as a sensor of flow and osmolality in renal epithelial cells. Am J Physiol Renal Physiol 293:F1699–F1713. doi: 10.1152/ajprenal.00462.2006 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Sylvie Janas
    • 1
  • François Seghers
    • 2
    • 8
  • Olivier Schakman
    • 2
  • Mohammad Alsady
    • 3
  • Peter Deen
    • 3
  • Joris Vriens
    • 4
  • Fadel Tissir
    • 5
  • Bernd Nilius
    • 6
  • Johannes Loffing
    • 7
  • Philippe Gailly
    • 2
  • Olivier Devuyst
    • 8
    Email author
  1. 1.Division of NephrologyUniversité catholique de Louvain Medical SchoolBrusselsBelgium
  2. 2.Laboratory of Cellular PhysiologyUniversité catholique de Louvain Medical SchoolBrusselsBelgium
  3. 3.Department of PhysiologyRadboud University Medical CenterNijmegenThe Netherlands
  4. 4.Laboratory of Experimental GynaecologyKatholieke Universiteit LeuvenLeuvenBelgium
  5. 5.Institute of NeuroscienceUniversité catholique de Louvain Medical SchoolBrusselsBelgium
  6. 6.Laboratory of Ion Channel ResearchKatholieke Universiteit LeuvenLeuvenBelgium
  7. 7.Institute of AnatomyUniversity of ZurichZurichSwitzerland
  8. 8.Institute of PhysiologyUniversity of ZurichZurichSwitzerland

Personalised recommendations