| BackgroundEssential hypertension is heterogeneous disease involved in which both genetics and environment factors influences blood pressure, which is a major risk factor for the cardiovascular disease. Therefore , to uncover the pathogenesis of essential hypertension is becoming more and more important. Epidemiological evidence supports a link between insulin resistance and hypertension. Insulin resistance leads to hyperinsulinemia. The high levels of insulin may play an important role in the pathogenesis of hypertension by stimulating the proliferation of vascular smooth muscle cells (VSMCs). Besides of the 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. Dopamine is an endogenous catecholamine that regulates/modu- lates many cellular functions, including effects on renal hemodynamics, ion and water transport and by regulation of hormones and humoral agent release, such as aldosterone, catecholamine, endothelin, prolactin, proopiomelanocortin, renin, and vasopressin. In addition, dopamine can control blood pressure by acting on cardiovascular centers, heart, and arterial and venous vessels. Dopamine exerts its actions by occupation of the D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors. The natriuretic and diuretic effects of dopamine receptors are confirmed in receptor null mice. In the hypertensive states, the dopamine receptors 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 study showed that, although D1 or D3 receptor had no effect on VSMC proliferation, it reduced norepinephrine or insulin-mediated VSMCs proliferation, stimulation of D1 or D3 receptor decreases insulin receptor expression, As a major subtype of D2-like receptors, D4 receptor exists in the heart, renal afferent artery, efferent artery, pulmonary artery, mesenteric artery, Whether D4 receptor has some effect on insulin receptor is not known, we hypothesized that D4 receptor may have an inhibitory effect on insulin receptor expression and function.We also found that D3 receptor agonist (PD128907) induced natriuresis in WKY rats on normal or high NaCl diet, An ETB receptor antagonist (BQ788), which, by itself, did not have a significant effect on sodium excretion, partially blocked the natriuretic effect of the D3 receptor agonist; Activation of D4 receptor affected ETB, AT1, insulin receptror expression in RPT cells. Based on those evidences, we hypothesize that D3 receptors, may have effects on ETB receptor expression and function in RPT cells, the impaired interaction might be involved into the pathogenesis of essential hypertension. Uncover of these issues will be helpful to elucidate the renal and arterial receptors interactions, to provide therapeutic target for normalization of the impaired receptor interaction in hypertensive states.ObjectiveTo uncover the interactions between dopamine receptor and other receptors (ETB receptor, insulin receptor), to explore the role of impaired interaction in essential hypertension. Methods1. Effects of D4 receptor on vascular insulin receptor expression and function and its mechanisms by cell number counting, uptake of MTT, reverse transcription-PCR, immunoblotting, and immunohistochemistry .2. Effects of D3 receptor on renal ETB receptor expression and function, its mechanisms by immunoblotting and measuring Na+-K+-ATPase activity.3. The interaction between D4 receptor and insulin receptor, D3 receptor and ETB receptor were determined by laser confocal microscopy and co-immunoprecipitation.Results1. D4 receptor, by itself, had no effect on VSMC proliferation. However, it could reduce insulin-mediated VSMC proliferation in A10 cells. The inhibitory effect of D4 receptor still existed in spontaneously hypertensive rats (SHRs).2. D4 receptor agonist, PD168077, decreased insulin receptor expression in a concentration-dependent and time-dependent manner, the inhibitory effect was via PKA. When actinomycin D was used to block the synthesis of new RNA, we found that D4 receptor increased insulin receptor degradation, which might be involved into the mechanism of D4 inhibitory of insulin receptor expression.3. There was co-localization and co-immunoprecipitation between D4 and insulin receptors, stimulation of D4 receptor decreased the linkage between D4 and insulin receptors.4. In WKY RPT cells, the D3 receptor agonist, PD128907, increased ETB receptor protein expression in a concentration-dependent and time-dependent manner, the effect was blocked in the presence of nicardipine. In contrast, in SHR RPT cells, PD128907, decreased ETB receptor protein expression.5. Basal D3/ETB receptor co-immunoprecipitation was greater in WKY than SHRs, The absolute amount of D3/ETB receptor co-immunoprecipitation induced by D3 receptor agonist was also greater in WKY than SHRs.6. Stimulation of ETB receptor decreased Na+-K+-ATPase activity in WKY but not in SHR cells. Pretreatment with PD128907 augmented the inhibitory effect of BQ3020 on Na+-K+-ATPase activity in WKY but not in SHR cells.ConclusionsDopamine receptor can affected vascular insulin receptor, renal ETB receptor expression and founction. Activation of D4 receptor inhibits insulin receptor expression and insulin-mediated VSMC proliferation both in Wistar-Kyoto and SHRs, which might be a new target to reduce the effects of insulin resistance on artery in hypertensive states. D3 receptor regulate ETB receptor by physical receptor interaction and govern receptor expression and founction, D3 receptor regulation of ETB receptor is aberrant in RPT cells from SHRs. |
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