The renal dopaminergic system: novel diagnostic and therapeutic approaches in hypertension and kidney disease

Salt sensitivity of blood pressure, whether in hypertensive or normotensive subjects, is associated with increased cardiovascular risk and overall mortality. Salt sensitivity can be treated by reducing NaCl consumption. However, decreasing salt intake in some may actually increase cardiovascular risk, including an increase in blood pressure, that is, inverse salt sensitivity. Several genes have been associated with salt sensitivity and inverse salt sensitivity. Some of these genes encode proteins expressed in the kidney that are needed to excrete a sodium load, for example, dopamine receptors and their regulators, G protein–coupled receptor kinase 4 (GRK4). We review here research in this field that has provided several translational opportunities, ranging from diagnostic tests to gene therapy, such as (1) a test in renal proximal tubule cells isolated from the urine of humans that may determine the salt-sensitive phenotype by analyzing the recruitment of dopamine D1 receptors to the plasma membrane; (2) the presence of common GRK4 gene variants that are not only associated with hypertension but may also be predictive of the response to antihypertensive therapy; (3) genetic testing for polymorphisms of the dopamine D2 receptor that may be associated with hypertension and inverse salt sensitivity and may increase the susceptibility to chronic kidney disease because of loss of the antioxidant and anti-inflammatory effects of the renal dopamine D2 receptor, and (4) in vivo renal selective amelioration of renal tubular genetic defects by a gene transfer approach, using adeno-associated viral vectors introduced to the kidney by retrograde ureteral infusion.