Renal medullary COX-2 in blood pressure control

描述（申请人提供）：已证实肾髓质具有降压功能，可能是多种自分泌和旁分泌因子（包括前列腺素、一氧化氮、内皮素等）协同作用的结果。肾髓质前列腺素，像许多其他的利钠因子一样，能够增加其合成速率以响应过量的盐，并促进钠和水的排泄。与这一观点一致，我们发现慢性盐负荷显著刺激肾髓质中COX-2的表达，髓内输注COX-2阻滞剂NS-398可显著降低尿流率。这些观察结果强烈表明肾髓质COX-2参与钠平衡和血压控制。大量临床试验表明，水肿是COX-2抑制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COX-2阻滞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COX-2的抑制。我们推测，在体液平衡状态改变的情况下，肾髓质COX-2的表达会发生动态变化，以调节尿钠排泄以稳定血压，并且COX-2与一氧化氮和内皮素等其他利钠因子相互作用，协调其利钠作用。为了验证这些假设，我们提出以下具体目的：1)探讨高盐诱导肾髓质COX-2表达在钠平衡和血压调节中的作用和机制；2)探讨肾髓质COX-2和一氧化氮系统在钠平衡和血压调节中的相互作用；3)探讨肾髓质COX-2和内皮素- b受体在钠平衡和血压调节中的相互作用。这些研究有望确定肾髓质COX-2的降压功能，并确定各种降压/利钠因子之间的相互关系。这些研究结果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.