The objective of this study is to identify the mechanisms of dopamine (DA)-mediated regulation of natriuresis in aging. DA is an endogenous natriuretic hormone that regulates salt reabsorption in the kidney proximal tubules by inhibiting apical membrane sodium-hydrogen exchanger-3 (NHE3) and basolateral membrane sodium-potassium ATPase (NKA). Regulated activities of NHE3 and NKA is critical for total body salt, water and mineral homeostasis and therefore contributes significantly to control of blood pressure, cardiac function, nerve impulses, and bone metabolism. We have demonstrated that expression of a sodium-hydrogen regulatory factor (NHERF-1) is essential for DA- mediated regulation of NKA. In cells lacking NHERF expression, DA fails to regulate NKA function. We demonstrated that NHERF-1 associates with NKA, Dopamine 1 receptor (D1 receptors), and PKC?. Upon stimulation with DA, NHERF-1 association with NKA decreased while association with D1 receptor and PKC? increased. Activation of protein kinase A (PKA) and C (PKC) by DA increases NHERF-1 phosphorylation at serine-77. Herein, we propose that phosphorylation of NHERF-1 allows it to leave the complex allowing NKA phosphorylation and endocytosis. Further, we hypothesize that in aging the loss of NHERF-1 - D1R interaction is responsible for salt-sensitive hypertension. We will address this hypothesis in two specific aims.
In Aim 1, we will compare NHERF-1 expression and phosphorylation in vehicle and dopamine treated FBN rats. We will determine the association of NHERF-1 to NKA, D1 and D5 receptors, PKA, and PKC?.
In Aim 2, we will treat NHERF-1 knock-out animals with high salt or dopamine and determine the importance of NHERF-1 in salt-sensitive hypertension in aging. We anticipate that these studies will provide new insights into the regulation of renal proximal tubular NHE3 and NKA by DA and provide potential therapeutic targets for treatment of disorders associated with abnormal sodium homeostasis in aging.

Public Health Relevance

Dopamine, an endogenous natriuretic hormone, inhibits the activities of both NHE3 and NKA thereby controlling blood pressure through increasing salt excretion in conditions of salt load. However, this mechanism is impaired in aging. We will study the mechanisms of sodium homeostasis and blood pressure in aging.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG047474-01A1
Application #
8770430
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Murthy, Mahadev
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40202
Muradashvili, Nino; Khundmiri, Syed Jalal; Tyagi, Reeta et al. (2014) Sphingolipids affect fibrinogen-induced caveolar transcytosis and cerebrovascular permeability. Am J Physiol Cell Physiol 307:C169-79