Purpose: 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 neurosectory cells that secrete vasopressin into circulation. Our studies will be among the first to test the role of the BDNF-TrkB signaling in an animal model of inappropriate vasopressin release. We propose that in an animal model of liver failure activity pendent stimulation of the BDNF-TrkB system increases vasopressin release by changing chloride transport preventing or reversing Cl- inhibition. Our hypotheses will be tested with the following Specific Aims: 1. To determine if norepinephrine inputs support chronic activation of AVP neurons in the SON of male bile duct ligated rats. 2. To determine if BDNF links the increased activation of AVP neurons to the changes in chloride transport loss of inhibition. 3. To test the role of estrogen in preventing AVP release in female BDL rats. 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, DREADD, shRNA site-specific knockdown, and in vitro electrophysiology to test these hypotheses. Benefit: These experiments will address an existing gap in our understanding of neurophypophyseal 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.

Public Health Relevance

The physiological mechanisms that cause fluid retention associated with liver disease are unknown. These studies focus on the brain's ability to regulate the release of the hormone vasopressin that is abnormally elevated causing fluid retention in patients with liver failure. Animal models of cirrhosis will be used to determine the physiological and cellular mechanisms that produce inappropriate vasopressin and fluid retention associated with liver failure to address this gap in our understanding and eventually to identify new therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL142341-03
Application #
9895545
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
OH, Youngsuk
Project Start
2018-04-15
Project End
2022-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of North Texas
Department
Internal Medicine/Medicine
Type
Graduate Schools
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Balapattabi, Kirthikaa; Little, Joel T; Farmer, George E et al. (2018) High salt loading increases brain derived neurotrophic factor in supraoptic vasopressin neurones. J Neuroendocrinol 30:e12639
Farmer, George E; Balapattabi, Kirthikaa; Bachelor, Martha E et al. (2018) AT1a influences GABAa mediated inhibition through the regulation of KCC2 expression. Am J Physiol Regul Integr Comp Physiol :