title: TRPV4 is associated with central rather than nephrogenic osmoregulation.
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.
authors.affiliation: Division of Nephrology, Université catholique de Louvain Medical School, 1200, Brussels, Belgium.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Janas
authors.affiliation: Laboratory of Cellular Physiology, Université catholique de Louvain Medical School, 1200, Brussels, Belgium.|Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Seghers
authors.affiliation: Laboratory of Cellular Physiology, Université catholique de Louvain Medical School, 1200, Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Schakman
authors.affiliation: Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alsady
authors.affiliation: Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Deen
authors.affiliation: Laboratory of Experimental Gynaecology, Katholieke Universiteit Leuven, 3000, Leuven, Belgium.
authors.forename: Joris
authors.initials: J
authors.lastname: Vriens
authors.affiliation: Institute of Neuroscience, Université catholique de Louvain Medical School, 1200, Brussels, Belgium.
authors.forename: Fadel
authors.initials: F
authors.lastname: Tissir
authors.affiliation: Laboratory of Ion Channel Research, Katholieke Universiteit Leuven, 3000, Leuven, Belgium.
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.affiliation: Institute of Anatomy, University of Zurich, CH-8057, Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.affiliation: Laboratory of Cellular Physiology, Université catholique de Louvain Medical School, 1200, Brussels, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gailly
authors.affiliation: Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland. olivier.devuyst@uzh.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism / Q000502:physiology; D004232:Diuretics / Q000494:pharmacology; D005665:Furosemide / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064587:Osmoregulation; D017673:Sodium Chloride, Dietary / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D014667:Vasopressins / Q000097:blood* / Q000378:metabolism
chemical_list: D000418:Albumins; D004232:Diuretics; D017673:Sodium Chloride, Dietary; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D014667:Vasopressins; D005665:Furosemide
keywords: Osmoregulation; TRPV4; Thirst; Tubular functions; Vasopressin