Renal medullary COX-2 in blood pressure control

描述（由申请人提供）：已确定肾髓质具有抗高血压功能，这可能是通过多种自分泌和旁分泌因子（包括肾上腺素、一氧化氮、内皮素等）的协调作用实现的。肾髓质肾上腺素与许多其他利钠因子一样，能够响应过量盐增加其合成速率，并促进钠和水排泄。与此一致，我们发现慢性盐负荷显著刺激肾髓质中考克斯-2的表达，髓内输注考克斯-2阻断剂NS-398显著降低尿流率。这些观察结果强烈表明肾髓质考克斯-2参与钠平衡和血压控制。大量临床试验表明，水肿是考克斯-2抑制剂最常见的部位效应之一。动物研究的实验数据表明，全身给予考克斯-2阻断剂可减少尿钠排泄并升高血压，这些作用可能是由于肾髓质中考克斯-2的抑制。我们推测，在液体平衡的变化状态下，肾髓质考克斯-2的表达发生动态变化，以调节尿钠排泄，以稳定血压，并且考克斯-2与其他利钠因子如一氧化氮和内皮素相互作用，以协调其利钠作用。为验证上述假说，我们提出以下具体目的：1）研究高盐诱导的肾髓质考克斯-2表达在钠平衡和血压调节中的作用及机制; 2）研究高盐诱导的肾髓质考克斯-2和一氧化氮系统在钠平衡和血压调节中的相互作用;肾髓质考克斯-2与内皮素-B受体在血压调节中的相互作用。这些研究将有助于明确肾髓质考克斯-2的降压功能和各种降压/利钠因子之间的相互关系。从这些研究中获得的信息将为长期控制动脉血压的分子机制提供新的见解。

DESCRIPTION (provided by applicant): It is established that renal medulla possesses antihypertensive function that is likely accomplished by the coordinated action of multiple autocrine and paracrine factors, including prostaglandins, nitric oxide, endothelins, etc. Renal medullary prostaglandins, like many other natriuretic factors, are capable of increasing their synthesis rate in response to excess salt and promote sodium and water excretion. In consistent with this notion, we found that COX-2 expression in renal medulla is remarkably stimulated by chronic salt loading and intramedullary infusion of COX-2 blocker NS-398 significantly reduces urine flow rate. These observations strongly indicate involvement of renal medullary COX-2 in sodium balance and blood pressure control. Large numbers of clinical trials have shown that edema is among the most common site effects of COX-2 inhibition. Experimental data from animal studies indicate that systemic administration of COX-2 blockers reduces urinary sodium excretion and increases blood pressure, and these effects are likely due to inhibition of COX-2 in renal medulla. We hypothesize that under changing states of fluid balance, renal medullary COX-2 undergoes dynamic changes in its expression in order to adjust urinary sodium excretion to stabilize blood pressure and that COX-2 interacts with other natriuretic factors such as nitric oxide and endothelins to coordinate their natriuretic actions. To test the hypotheses, we propose the following Specific Aims: 1) investigate the role and mechanism of high salt-induced renal medullary COX-2 expression in sodium balance and blood pressure regulation; 2) investigate the interaction of renal medullary COX-2 and nitric oxide system in sodium balance and blood pressure regulation; and 3) investigate the interaction of renal medullary COX-2 and endothelin-B receptor in sodium balance in blood pressure regulation. These studies are expected to establish the antihypertensive function of renal medullary COX-2 and to define the interrelationship among various depressor/natriuretic factors. The information resulted from these studies will provide new insight into the molecular mechanism responsible for long-term control of arterial blood pressure.