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Abnormal osmotic regulation in trpv4-/- mice.

ABSTRACT: Osmotic homeostasis is one of the most aggressively defended physiological parameters in vertebrates. However, the molecular mechanisms underlying osmotic regulation are poorly understood. The transient receptor potential channel, vanilloid subfamily (TRPV4), is an osmotically activated ion channel that is expressed in circumventricular organs in the mammalian CNS, which is an important site of osmotic sensing. We have generated trpv4-null mice and observed abnormalities of their osmotic regulation. trpv4-/- mice drank less water and became more hyperosmolar than did wild-type littermates, a finding that was seen with and without administration of hypertonic saline. In addition, plasma levels of antidiuretic hormone were significantly lower in trpv4-/- mice than in wild-type littermates after a hyperosmotic challenge. Continuous s.c. infusion of the antidiuretic hormone analogue, dDAVP, resulted in systemic hypotonicity in trpv4-/- mice, despite the fact that their renal water reabsorption capacity was normal. Thus, the response to both hyper- and hypoosmolar stimuli is impaired in trpv4-/- mice. After a hyperosmolar challenge, there was markedly reduced expression of c-FOS in the circumventricular organ, the organum vasculosum of the lamina terminalis, of trpv4-/- mice compared with wild-type mice. This finding suggests that there is an impairment of osmotic sensing in the CNS of trpv4-/- mice. These data indicate that TRPV4 is necessary for the normal response to changes in osmotic pressure and functions as an osmotic sensor in the CNS.

SUBMITTER: Liedtke W

PROVIDER: S-EPMC263876 | biostudies-literature | 2003 Nov

REPOSITORIES: biostudies-literature

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Abnormal osmotic regulation in trpv4-/- mice.

Liedtke Wolfgang W Friedman Jeffrey M JM

Proceedings of the National Academy of Sciences of the United States of America 20031027 23

Osmotic homeostasis is one of the most aggressively defended physiological parameters in vertebrates. However, the molecular mechanisms underlying osmotic regulation are poorly understood. The transient receptor potential channel, vanilloid subfamily (TRPV4), is an osmotically activated ion channel that is expressed in circumventricular organs in the mammalian CNS, which is an important site of osmotic sensing. We have generated trpv4-null mice and observed abnormalities of their osmotic regulat ...[more]

PMID: 14581612

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Project description:Painful intervertebral disc (IVD) degeneration is an age-related process characterized by reduced tissue osmolarity, increased catabolism of the extracellular matrix, and elevated levels of pro-inflammatory molecules. With the aging population and constantly rising treatment costs, it is of utmost importance to identify potential therapeutic targets and new pharmacological treatment strategies for low back pain. Transient receptor potential (TRP) channels are a family of Ca2+ permeable cell membrane receptors, which can be activated by multitude of stimuli and have recently emerged as contributors to joint disease, but were not investigated closer in the IVD. Based on the gene array screening, TRPC1, TRPM7, and TRPV4 were overall the most highly expressed TRP channels in bovine IVD cells. We demonstrated that TRPV4 gene expression was down-regulated in hypo-osmotic condition, whereas its Ca2+ flux increased. No significant differences in Ca2+ flux and gene expression were observed for TRPM7 between hypo- and iso-osmotic groups. Upon hypo-osmotic stimulation, we overall identified via RNA sequencing over 3,000 up- or down-regulated targets, from which we selected aggrecan, ADAMTS9, and IL-6 and investigated whether their altered gene expression is mediated through either the TRPV4 or TRPM7 channel, using specific activators and inhibitors (GSK1016790A/GSK2193874 for TRPV4 and Naltriben/NS8593 for TRPM7). GSK1016790A induced the expression of IL-6 under iso-osmotic condition, alike to hypo-osmotic stimulation alone, indicating that this effect might be TRPV4-mediated. However, using the TRPV4 blocker GSK2193874 failed to prevent the increase of IL-6 under hypo-osmotic condition. A treatment with TRPM7-activator did not cause significant changes in the gene expression of tested targets. In conclusion, while TRPV4 and TRPM7 are likely involved in osmosensing in the IVD, neither of them mediates hypo-osmotically-induced gene expression changes of aggrecan, ADAMTS9, and IL-6.

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Abnormal osmotic regulation in trpv4-/- mice.

Publications

Abnormal osmotic regulation in trpv4-/- mice.

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