Mice lacking TRPV4 show abnormal thirst regulation in absence of renal defects

TRPV4 is a polymodal cation channel of the transient receptor potential (TRP) family. It is expressed in hypothalamic neurons including the subfornical organ, median preoptic area, and the organum vasculosum of the lamina terminalis, where it could play a role in osmotic sensing. TRPV4 has also been evidenced in the thick ascending limb (TAL) of the rat nephron, where its role remains unclear. To further analyze the role of TRPV4 in osmoregulation, we investigated its distribution pattern and the functional consequences of its disruption in mouse. Using qPCR on microdissected segments and immunohistochemistry, we found that TRPV4 is abundantly expressed in the proximal tubules (apical and basolateral), late distal convoluted tubules and throughout the connecting tubules and collecting ducts (basolateral), including principal and intercalated cells. By contrast, TRPV4 was undetectable in glomeruli and TAL, and weakly abundant in early DCT. Metabolic studies in 12 weeks old TRPV4 knock-out (KO) and wild-type (WT) mice revealed that disruption of TRPV4 does not influence renal function and urinary concentration at baseline. The KO mice did not exhibit anomalies in activity, rearing, food and water intake. Moreover, both WT and KO mice showed a similar renal NaCl and water excretion in response to furosemide injection, acute water loading (100 l/g BW i.p.), overnight water deprivation, and chronic dietary NaCl restriction (17 days, 0.01% NaCl),. However, acute administration of hypertonic saline solution (0.5 M NaCl) resulted in a significantly lower water intake in the TRPV4 KO vs WT mice, suggesting a central defect in osmoregulation. These results demonstrate that TRPV4 is widely expressed in the mouse kidney, but not in the TAL. Disruption of TRPV4 is not reflected by significant alterations in the renal handling of NaCl and water. However, TRPV4 KO mice show a decreased thirst response to hypertonic NaCl, which substantiates the major role of TRPV4 in the central regulation of osmolality