Regulation of Cylooxygenase-2 in Macula Densa and cTALH

致密斑和 cTALH 中环氧合酶 2 的调节

• 批准号: 6556920
• 负责人: RAYMOND C. HARRIS
• 金额: $ 35.49万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-20 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6556920
• 关键词: chloride ion; eicosanoid metabolism; laboratory mouse; laboratory rabbit; laboratory rat; phospholipase A2; prostaglandin endoperoxide synthase; renal tubular transport; renal tubule; renin; renin angiotensin system; tissue /cell culture; transforming growth factors; vascular endothelium

DESCRIPTION (provided by applicant): Prostaglandins regulate vascular tone and salt and water homeostasis in the mammalian kidney and are involved in the mediation and/or modulation of hormonal action. Cyclooxygenase (prostaglandin synthase G2/H2) is the rate-limiting enzyme in metabolism of arachidonic acid to prostaglandin G2 and subsequently to prostaglandin H2, which serves as precursor for subsequent metabolism by prostaglandin and thromboxane synthetases.lt is now recognized that cyclooxygenase-2 (COX-2) is highly expressed in the macula densa and surrounding cortical thick ascending limb (cTAL) of mammalian kidney and is involved in regulation of renin expression and secretion. Our studies in primary cultured cTALH have indicated that COX-2 expression is increased in response to decreased extracellular chloride by a p38 dependent process. There are three specific aims in the current proposal. In the first aim, we will examine mechanisms of regulation of COX-2 expression in macula densa/cTAL. We hypothesize that decreased extracellular chloride increases COX-2 expression in cTAL/macula densa by cell shrinkage and/or by decreases in intracellular chloride, which will activate PLA2activity and release prostaglandins that activate p38 activity. We further hypothesize that COX-2 increases both by NF-kappa B-mediated transcriptional activation and by increased mRNA stability. The second specific aim will investigate the modulation of cTAL/macula densa COX-2 expression by the renin-angiotensin system and nitric oxide. We hypothesize that these agonists modulate COX-2 expression by altering chloride flux and thereby modulating p38 activity. The third specific aim will investigate the modulation of renin expression by COX-2. In these studies, we will examine the regulation of prostaglandin synthases in high renin states and examine the interaction of COX-2 metabolites and TGF beta 2 in regulation of renin expression. We also propose to develop mice with selective deletion of COX-2 in the endothelium to determine the role of endothelial-generated COX-2 metabolites in regulation of renin expression and secretion. In summary, these studies will provide further insight into regulatory mechanisms of renal corticalCOX-2 expression and physiologic roles of COX-2-generated metabolites in regulation of the renin-angiotensin system.

描述（由申请人提供）：前列腺素调节哺乳动物肾脏中的血管张力以及盐和水稳态，并参与激素作用的介导和/或调节。环加氧酶（前列腺素合酶 G2/H2）是花生四烯酸代谢为前列腺素 G2 并随后代谢为前列腺素 H2 的限速酶，前列腺素 H2 是前列腺素和血栓素合成酶后续代谢的前体。现在人们认识到环加氧酶-2 (COX-2) 具有高度催化活性。 在哺乳动物肾脏的致密斑和周围皮质厚升肢 (cTAL) 中表达，参与肾素表达和分泌的调节。我们对原代培养的 cTALH 的研究表明，通过 p38 依赖性过程，COX-2 表达因细胞外氯减少而增加。当前提案中有三​​个具体目标。第一个目标是，我们将研究密集黄斑/cTAL 中 COX-2 表达的调节机制。我们假设细胞外氯离子减少会通过细胞收缩和/或细胞内氯离子减少来增加 cTAL/致密斑中 COX-2 的表达，这将激活 PLA2 活性并释放激活 p38 活性的前列腺素。我们进一步假设 COX-2 通过 NF-κ B 介导的转录激活和 mRNA 稳定性的增加而增加。第二个具体目标是研究肾素-血管紧张素系统和一氧化氮对 cTAL/致密斑 COX-2 表达的调节。我们假设这些激动剂通过改变氯离子通量来调节 COX-2 表达，从而调节 p38 活性。第三个具体目标是研究 COX-2 对肾素表达的调节。在这些研究中，我们将检查高肾素状态下前列腺素合酶的调节，并检查 COX-2 代谢物和 TGF beta 2 在肾素表达调节中的相互作用。我们还建议开发选择性删除内皮细胞中COX-2的小鼠，以确定内皮生成的COX-2代谢物在调节肾素表达和分泌中的作用。总之，这些研究将进一步深入了解肾皮质COX-2表达的调节机制以及COX-2生成的代谢物在肾素-血管紧张素系统调节中的生理作用。