Our study focuses on genetic variations in G protein-related kinase 4 (GRK4) and encoding the sodium-bicarbonate co-transporter (SLC4A5) that our previous studies have indicated play a role in salt sensitivity of blood pressure.  The goal of this study is to determine the relationship between these gene variants and salt sensitivity in humans. Our hypothesis is that individuals with polymorphisms in both GRK4 and SLC4A5 copies will be salt sensitive, salt resistant, or inverse salt sensitive.

We define salt sensitivity as changes in blood pressure that parallel salt intake. Studies have shown that salt sensitivity itself is a risk factor for cardiovascular events separate from hypertension. Learning more about the diagnosis of salt sensitivity,  salt resistance, and inverse salt sensitivity can help physicians better manage patients’ hypertension based on genetic predisposition.

GRK4 is a protein that acts in the dopaminergic system of the kidney.  The kidney has endogenous dopamine made from circulating (and filtered) L-DOPA in the proximal tubule cells. Through a signaling cascade using dopamine receptors, mainly the D1 receptor, activation of the dopaminergic system leads to natriuresis.  

Binding of dopamine to the G-protein-coupled D1 receptor specifically promotes natriuresis by inhibition of NHE-3, Na/HCO3 cotransporter, and NaKATPase activity; dopamine’s actions are mainly in the proximal tubule of the kidney. This system is activated when sodium intake is high.

The renin-angiotensin system interacts with the dopamine system through the coupling of the AT2 receptor and D1 receptor in which the D1 receptor is dependent on the AT2 receptor for its natriuretic action. The net actions of both receptors acting in concert leads to natriuresis and lowering of blood pressure.Activation of this pathway also leads to recruitment of additional receptors .Current studies are underway to further examine the relationship between these two receptors.

The SLC4A5 gene product is a sodium-bicarbonate cotransporter in the renal tubule cells. Certain variants in this gene are associated with salt sensitivity.  We are continuing to learn about the mechanism of SLC4A5 but know it is important in the control of blood pressure in humans.