Fluid-electrolyte disorders are prevalent in our society, and even mild disorders are associated with poor outcomes. A key component of body fluid regulation is largely through control of water reabsorption by the renal collecting duct (CD) via the actions of vasopressin. The aquaporins (AQPs) are a large family of water channels expressed throughout the body. In the CD, there is apical expression of AQP2 and basolateral expression of AQP3 and AQP4 that regulate transcellular water reabsorption. AQP2 and AQP3 are vasopressin-sensitive, and genetic deletion of either of these water channels results in severe polyuria and a urinary concentrating defect. Compared to AQP2, we know little about the regulation of AQP3 function. We recently determined that AQP3 can be post-translationally lysine (K) acetylated at K282. Acetylated AQP3 (acAQP3) is expressed in the basolateral membrane of the CD and is increased with water deprivation in both male and female mice. Moreover, acAQP3 expression increases in the inner medullary collecting duct with dehydration. Our central hypothesis is that lysine acetylated AQP3 is critical for maintaining fluid balance during water deprivation. Our preliminary data suggest that the acetyltransferases CBP (CREB Binding Protein) and EP300 interact and lysine acetylate AQP3. The focus of our ?intracellular signaling aim? is to test the hypothesis that vasopressin activates CBP and EP300 resulting in lysine acetylation of AQP3. We will also determine the functional significance of this novel post-translational modification. The goal of the ?physiology aim? is to test the hypothesis that acetylation of AQP3 results in anti-diuresis. Identification of acetylation of AQP3 K282 provides a new target for therapeutic interventions to treat water balance disorders. The data, reagents, tools, and mice generated from this application are key for the successful submission and subsequent funding of my R01 within the next two years.

Public Health Relevance

Body fluid homeostasis is maintained through the actions of vasopressin-mediated water reabsorption via the apical AQP2 and basolateral AQP3 in the collecting duct. We recently discovered that AQP3 is lysine acetylated, which is the first ever report of a post-translational modification of AQP3. The goals of this study are to determine the regulation and physiological function of AQP3 lysine acetylation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK120503-01
Application #
9702260
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2019-04-01
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294