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TRPV4 is associated with central rather than nephrogenic osmoregulation

  • Organ physiology
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Abstract

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.

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Acknowledgments

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.

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    Authors and Affiliations

    1. Division of Nephrology, Université catholique de Louvain Medical School, 1200, Brussels, Belgium

      Sylvie Janas

    2. Laboratory of Cellular Physiology, Université catholique de Louvain Medical School, 1200, Brussels, Belgium

      François Seghers, Olivier Schakman & Philippe Gailly

    3. Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands

      Mohammad Alsady & Peter Deen

    4. Laboratory of Experimental Gynaecology, Katholieke Universiteit Leuven, 3000, Leuven, Belgium

      Joris Vriens

    5. Institute of Neuroscience, Université catholique de Louvain Medical School, 1200, Brussels, Belgium

      Fadel Tissir

    6. Laboratory of Ion Channel Research, Katholieke Universiteit Leuven, 3000, Leuven, Belgium

      Bernd Nilius

    7. Institute of Anatomy, University of Zurich, CH-8057, Zurich, Switzerland

      Johannes Loffing

    8. Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland

      François Seghers & Olivier Devuyst

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    Philippe Gailly and Olivier Devuyst co-directed the study and are co-senior authors.

    Sylvie Janas and François Seghers contributed equally to this work.

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    Janas, S., Seghers, F., Schakman, O. et al. TRPV4 is associated with central rather than nephrogenic osmoregulation. Pflugers Arch - Eur J Physiol 468, 1595–1607 (2016). https://doi.org/10.1007/s00424-016-1850-5

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