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

Abstract

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, i.e., 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, e.g., dopamine receptors and their regulators, 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) 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 anti-oxidant 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 AAV vectors introduced to the kidney by retrograde ureteral infusion.

Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure

“…Mice with intrarenal dopamine deficiency have increased oxidative stress and infiltration of inflammatory cells (12), and decreased renal dopamine production is associated with increased detrimental effects of angiotensin II on renal injury (13). The antiinflammatory effects of dopamine are mediated, at least in part, by the dopamine D2 receptor (DRD2) (14–18) that is expressed in proximal and distal convoluted tubules, collecting ducts, and glomerular mesangial cells (19). Lack or downregulation of DRD2 function in mice increases renal expression of proinflammatory cytokines/chemokines, resulting in histological and functional evidence of renal inflammation and injury, suggesting that the DRD2 has protective effects in the kidney by limiting the inflammatory reaction (15).…”

Kidney tubules

“…2). D 1 -like receptors inhibit salt and water transport in tubular cells, relax vascular smooth muscle, and inhibit sympathetic nervous system activity [34,35]. Stimulation of D 1 -like receptors is associated with natriuresis and diuresis in states of sodium loading, without a requirement for increased renal blood flow [36,37].…”

“…Studies examining polymorphisms within the human D 2 receptor gene have shown a correlation with hypertension in clinical cohorts [35]. Mice lacking D 2 receptors exhibit worsened renal injury and fibrosis independent of BP, with miRNA 214 implicated as pathogenic [39,40▪].…”

L-Tyr-Induced Phosphorylation of Tyrosine Hydroxylase at Ser⁴⁰: An Alternative Route for Dopamine Synthesis and Modulation of Na⁺/K⁺-ATPase in Kidney Cells

“…In the central nervous system (CNS), where these hormones have been extensively studied, the presence of DA is differentially distributed within brain structures, the striatum containing the highest number of dopaminergic neurons [1]. Beyond its well-established role in the CNS, DA emerged 20 years ago as an important modulator of peripheral organs, being their kidney actions of great importance, which support the view that DA can be considered an intrarenal natriuretic hormone [2, 3] of potential therapeutic significance [4]. …”