The Role of Dopamine D2 receptors and Oxidative Stress in the Pathogenesis of Hypertension

Globally, hypertension is the number one risk factor for death, affecting more than 1 billion people. Hypertension is the result of the interactions among genetics, epigenetics, environment, and lifestyle. The long-term regulation of blood pressure rests on renal and non-renal mechanisms. The impaired renal sodium handling in hypertension is caused by aberrant counter-regulatory natriuretic/anti-natriuretic pathways. The sympathetic nervous and renin-angiotensin systems are anti-natriuretic pathways. A counter-regulatory natriuretic pathway is the renal dopaminergic system. Aberrant dopaminergic regulation of renal sodium transport in hypertension is caused by a decrease in renal dopamine synthesis and/or dysfunction of any of the 5 dopamine receptors (D1R, D2R, D3R, D4R, & D5R). Normally, an increase in sodium intake increases while a decrease in sodium intake decreases blood pressure, albeit transiently until sodium balance is achieved. However, ~50 % of hypertensive and ~26% of normotensive subjects have increased blood pressure on high sodium intake, a case of salt sensitivity, while ~20 % have increased blood pressure on a low sodium intake, a case of inverse salt sensitivity. Low and high sodium intakes are associated with increased incidence of cardiovascular events/mortality. In humans with inverse salt sensitivity, there is a linear relationship between the number of single nucleotide polymorphisms in DRD2 (rs6276 and 6277) and decreased renal D2R expression. The increase in blood pressure on a low sodium diet may be due to increased activities of the renin-angiotensin and sympathetic nervous systems that cannot be counteracted by D2R. Hypertension may be a cause or consequence of inflammation or oxidative stress. Deficient D2R function causes renal inflammation independently of the increase in blood pressure. Subjects carrying DRD2 single nucleotide polymorphisms have increased inflammation, mediated by decreased regulation of the miR-217-Wnt5a-Ror2 pathway. The D2R, via paraoxonase2 and sestrin2, maintains normal redox balance and blood pressure. In summary, the D2R is important in the maintenance of normal blood pressure by regulating renal sodium transport, vascular reactivity, inflammation, and redox balance.