Hypertension, the leading cause of cardiovascular disease (CVD) worldwide, affects nearly one in three adults in the United States and has been negatively associated with increased sodium consumption. High salt diets mediate an increase in sodium delivery and flow in the renal tubules, where nitric oxide synthase-1 (NOS1) has long been known to act as a key natriuretic factor. However, the mechanisms by which NOS1 activity is upregulated to promote nitric oxide (NO) production under high flow conditions is still elusive. The central hypothesis of the proposed studies is that, within renal inner-medullary collecting duct (IMCD) cells, high tubular flow leads to increased histone deacetylation 1 (HDAC1)- and cilia- mediated NOS1 upregulation that leads to increased nitric oxide production and, subsequently, effective natriuresis. In order to study the contribution of HDAC1, we will utilize mouse IMCD cells in vitro and ex vivo under acute flow conditions to elucidate the nature and location of interactions between HDAC1 and NOS1. HDAC1 inhibitor MS-275 and NOS1 site-specific lysine mutants will aid in pinpointing these connections. To determine the contribution of primary cilia, we will utilize cilia-deficient renal epithelial cells in vitro to illuminate the capability of cilia to activate NOS1 in response to flow and visualize the impact of mechanosensation via real-time simultaneous measurements of intracellular calcium signaling and NO production. Furthermore, fluid-electrolyte homeostasis will be examined using a collecting duct deficient mouse model (CDIFTKO). The long-term goal of this research is to harness the understanding of NOS1 activity to direct cardiovascular interventions beneficial to hypertension patients.

Public Health Relevance

Hypertension is often is linked to high sodium consumption, both of which promote significant cardiovascular disease complications. Increased nitric oxide production by renal inner-medullary collecting duct cells is an established mediator of natriuresis in response to increased dietary sodium consumption, and the proposed study will investigate two novel mechanisms which lead to increased renal nitric oxide production.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DK111067-02
Application #
9378058
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Rankin, Tracy L
Project Start
2016-08-05
Project End
2019-08-04
Budget Start
2017-08-05
Budget End
2018-08-04
Support Year
2
Fiscal Year
2017
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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Tran, Anh Nhat; Walker, Kiera; Harrison, David G et al. (2018) Reactive species balance via GTP cyclohydrolase I regulates glioblastoma growth and tumor initiating cell maintenance. Neuro Oncol 20:1055-1067