Hyponatremia is the most common electrolyte disorder and in 2006 the cost of treating hyponatremia in the US was estimated to be $1.6-$3.6 billion per year. Inappropriate vasopressin secretion is the major cause of dilutional hyponatremia associated with liver and heart failure. Brain derived neurotrophic factor (BDNF) and its receptor TrkB are expressed by magnocellular neurosecretory cells that secrete vasopressin into circulation. Our studies will be among the first to test the role of the BDNF-TrkB signaling in the homeostatic regulation of the neurohypophyseal system and in an animal model of inappropriate vasopressin release. We propose that activation of the BDNF-TrkB system increases vasopressin release by enhancing the postsynaptic effects of NMDA receptors on vasopressin release.
Specific Aim 1 : will test the role of neurohypophysial BDNF-TrkB signaling on the effects of water deprivation on neurohypophyseal function and vasopressin release. Hypothesis: Phosphorylation of TrkB associated with water deprivation leads to phosphorylation of NMDA receptor subunits through Fyn kinase, a downstream member of the Src kinase family. In these experiments we will test whether BDNF-trkB mediated neuroplasticity contribute to sustained vasopressin release produced by water deprivation.
Specific Aim 2 : will test the hypothesis that neurohypophysial BDNF-TrkB signaling contributes to inappropriate vasopressin release in an animal model of dilutional hyponatremia. Hypothesis: BDNF-TrkB mediated changes in NMDA receptor function contribute to changes in the osmotic and non-osmotic regulation of vasopressin neurons in rats with experimental induced hepatic cirrhosis. In these experiments, the bile duct ligation model of cirrhosis-induced hyponatremia will be used to test the role of the BDNF-TrkB signaling on SON neurons in the context of inappropriate vasopressin release. Methods: The studies will employ Western blot and co-immunoprecipitation in combination with immunohistochemistry and laser capture microdissection RT-PCR, metabolism cage studies to measure urine and sodium excretion, and in vitro electrophysiology to test these hypotheses. Benefit: These experiments will address an existing gap in our understanding of neurohypophyseal function and the pathogenesis of hyponatremia. The findings of these experiments could potentially alter the way that inappropriate vasopressin release is studied and conceptualized clinically.
The long term goal of this research program is to identify neural networks that control the release of vasopressin. Inappropriate vasopressin release related to heart failure or liver failure increases the morbidity and mortality of these patients 7 11. Hyponatremia related to vasopressin release is the most common electrolyte disorder and in 2006 the cost of treating hyponatremia in the US was estimated to be $1.6-$3.6 billion per year 12. This proposal will test a novel signaling pathway that regulates the activity of vasopressin neurons in health and disease that could identify new therapeutic targets for treating of inappropriate vasopressin release that could be addressed by FDA approved pharmaceuticals.
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|Nedungadi, T Prashant; Cunningham, J Thomas (2014) Differential regulation of TRPC4 in the vasopressin magnocellular system by water deprivation and hepatic cirrhosis in the rat. Am J Physiol Regul Integr Comp Physiol 306:R304-14|
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|Walch, Joseph D; CarreÃ±o, FlÃ¡via Regina; Cunningham, J Thomas (2013) Intracerebroventricular losartan infusion modulates angiotensin II type 1 receptor expression in the subfornical organ and drinking behaviour in bile-duct-ligated rats. Exp Physiol 98:922-33|
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