Water balance is maintained through the regulation of water reabsorption by the renal collecting duct (CD) via the vasopressin (AVP) regulated water channel aquaporin-2 (AQP2). Dysfunction in AQP2 leads to diseases such as nephrogenic diabetes insipidus (polyuria) or antidiuresis syndrome (water retention), and severe fluid retention is a common ailment in cardiovascular disease. Histone deacetylase enzymes (HDACs) remove acetyl groups from lysines of histones leading to epigenetic modification of gene transcription or non-histone proteins in a post-translational manner. There is growing interest in the therapeutic use of HDAC inhibitors in cardiovascular disease because of their anti- inflammatory properties. Interestingly, a reported side effect of HDAC inhibitor use is hyponatremia, suggesting these drugs affect fluid balance. Thus, it is imperative that we gain a better understanding of the role of HDACs in body fluid balance in order to avoid potentially dangerous side effects. Our compelling preliminary data support a novel role for HDAC1 regulation of diuresis by regulating transcription and deacetylation of proteins in the CD. Our central hypothesis is that during excess water consumption, HDAC1 mediates diuresis via regulation of AQP2 apical expression by directly deacetylating AQP2, indirectly by decreasing expression of the AVP subtype 2 receptor (V2R), and indirectly by increasing in nitric oxide synthase-1 (NOS1) derived nitric oxide (NO). The following hypotheses will be tested: 1) To test the hypothesis that water balance is maintained by changes in collecting duct AQP2 acetylation and apical surface expression; 2) To test the hypothesis that hydration promotes deacetylation of AQP2 and/or downregulation of the V2R receptor via HDAC1 in the CD, thus promoting diuresis; 3) To test the hypothesis that HDAC1-dependent increases in CD NO derived from NOS1 leads to decreases in AQP2 surface expression. With the help of mentor and advisory team, I will continue on the path towards my long term goal of developing a strong, independent, research program in the field of cardio/renal physiology with a focus on addressing novel mechanisms underlying cardio/renal diseases.

Public Health Relevance

Water balance is a fundamental physiological process that is controlled by the kidneys. Imbalances of body water are causally linked with kidney disease, which is a risk factor for the development of cardiovascular disease. The goal of this proposal is to reveal novel target pathways regarding the enzymes, histone deacetylases, and their regulation of proteins critical for maintaining water balance by the kidney.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK105038-05
Application #
9766242
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2015-09-01
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
5
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
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Speed, Joshua S; Hyndman, Kelly A; Roth, Kaehler et al. (2018) High dietary sodium causes dyssynchrony of the renal molecular clock in rats. Am J Physiol Renal Physiol 314:F89-F98
Hyndman, Kelly A; Mironova, Elena V; Giani, Jorge F et al. (2017) Collecting Duct Nitric Oxide Synthase 1ß Activation Maintains Sodium Homeostasis During High Sodium Intake Through Suppression of Aldosterone and Renal Angiotensin II Pathways. J Am Heart Assoc 6:
Hyndman, Kelly A; Knepper, Mark A (2017) Dynamic regulation of lysine acetylation: the balance between acetyltransferase and deacetylase activities. Am J Physiol Renal Physiol 313:F842-F846
Speed, Joshua S; Hyndman, Kelly A (2016) In vivo organ specific drug delivery with implantable peristaltic pumps. Sci Rep 6:26251
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Hyndman, Kelly Anne; Dugas, Courtney; Arguello, Alexandra M et al. (2016) High salt induces autocrine actions of ET-1 on inner medullary collecting duct NO production via upregulated ETB receptor expression. Am J Physiol Regul Integr Comp Physiol 311:R263-71
Davenport, Anthony P; Hyndman, Kelly A; Dhaun, Neeraj et al. (2016) Endothelin. Pharmacol Rev 68:357-418