Role Of Dopamine Receptor And ETB/AT₁/Insulin Receptors Interaction In The Pathogenesis Of Essential Hypertension

BackgroundEssential hypertension affects 25% of the adult population and constitutes a major risk factor for stroke, myocardial infarction, heart failure, and kidney failure; therefore, to uncover the pathogenesis of essential hypertension is becoming more and more important. Besides of the central nervous system and artery, the kidney plays a role in the regulation of blood pressure by affecting sodium reabsorption. Among all segments, the effect of renal proximal tubule (RPT) is evident, which takes charge of 66% renal sodium reabsorption.It's known that sympathetic system takes an important position in the pathogenesis of essential hypertension. Based on those research results, some anti-hypertensive medicines are developed in the past years, such asβ- andα-receptor blockers. However, as a transmitter secreted from sympathetic nerve terminal, the function of dopamine and its receptor is not clear. Dopamine, works as a precursor of norepinephrine and epinephrine, can play direct effects on blood pressure by regulation of sodium excretion via dopamine receptor. When sodium is repleted, dopamine takes care of more than 50% sodium excretion. Based on pharmacologic characteristics, dopamine receptor is divided into two subtypes, D₁-like receptor (including D₁ and D5 receptors) and D₂-like receptor (D₂, D₃ and D4 receptors). The natriuretic and diuretic effects of dopamine receptor are confirmed in receptor null mice, in the hypertensive states, the dopamine receptor mediated natriuresis and diuresis are impaired.Apart from dopamine, the renal natriuresis and diuresis are also regulated by other humoral factors, such as sympathetic nervous system (including dopamine), endothelin, renin-angiotensin system. According to the effects on sodium excretion, those humoral factors are divided into two subfamilies, one family enhances; while the other inhibits sodium excretion. The interaction of those two subfamilies of humoral factors keeps sodium excretion and blood pressure in normal extent. Our previous studies found that there are mutual interactions between D₁, AT₁, ETB receptors, which are impaired in hypertensive states.A lot of studies focus on D₁-like receptor in the past years. As an important ingredient, how about the role of D₂-like receptor in the regulation of blood pressure. Is there any interaction between D₂-like receptor and other receptors? Our previous study found activation of D₁-like receptor and D₂-like receptor synergistically increases sodium excretion, stimulation of D₁ receptor increases D₃ receptor expression. Based on those evidences, we hypothesize that D₂-like receptors, especially D₃ and D4 receptors, have effects on renal AT₁ and ETB receptor expression and function, the impaired interaction among those receptors might be involved into the pathogenesis of essential hypertension. Moreover, the interaction between dopamine receptor and proliferative factors, such asα1-adrenergic receptor and insulin receptor, also will be investigated in this experiment. Uncover of those issues will be helpful to elucidate the renal and arterial interactions, to provide therapeutic target for normalization of the impaired receptor interaction in hypertensive states.ObjectiveTo uncover the interactions between dopamine receptor and other receptor (ETB receptor, AT₁ receptor, insulin receptor), to investigate the role of impaired interaction on essential hypertension.Investigation content1. Effects of D₁-like and D₃ receptors on vascular insulin receptor expression and function, its mechanisms and physiological significance.2. Effects of D₃ receptor on AT₁ receptor expression and function, its mechanisms and pathophysiological significance.3. The natriuretic effect of D₃ receptor in in-vivo experiment, the role of ETB receptor on the D₃ receptor-mediated natriuresis.4. To observe whether the above-mentioned interactions are aberrant in hypertensive states.Results1. Stimulation of D₁-like or D₃ receptor inhibited insulin receptor expression and its stimulatory effect on proliferation in VSMCs, the inhibitory effect of D₁-like receptor was via PKC and MEK, while the D₃ receptor via PKA.2. Activation of D₃ receptor inhibited AT₁ receptor protein or mRNA expression in RPT cells from WKY rats, in contrast, in SHR cells, activation of D₃ receptor increased AT₁ receptor expression. There was co-localization and co-immunoprecipitation between D₃ and AT₁ receptors, stimulation of D₃ receptor decreased the D₃ and AT₁ receptor co-immunoprecipitation, and the basal levels of D₃/AT₁ receptor co-immunoprecipitation was higher in WKY cells than in SHR cells.3. D₃ receptor agonist, PD128907, infused via renal artery, increased sodium excretion in WKY rats fed with low-, normal or high-salt diet, but not in SHRs. ETB receptor antagonist BQ788, by itself, had no effects on sodium excretion, but could partially inhibited D₃ receptor-mediated natriuretic effect in WKY rats.ConclusionActivation of dopamine receptor regulates renal and arterial ETB, AT₁ and insulin receptor expressions from WKY rats, whose effects are impaired in SHRs. The impaired interaction between dopamine receptor and other receptor might be involved into the pathogenesis of essential hypertension.