Supressor ANGII Determines Acute & Chronic Renal Injury

ANGII 抑制剂决定急性

• 批准号: 7145529
• 负责人: LUIS A. JUNCOS
• 金额: $ 30.34万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-04 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145529
• 关键词: acute renal failure; angiotensin /renin /aldosterone hypertension; angiotensin II; chronic disease /disorder; cytoprotection; dietary sodium; genetically modified animals; heme oxygenase; hemodynamics; hormone regulation /control mechanism; inflammation; injection /infusion; kidney circulation; kidney disorder; kidney pharmacology; laboratory mouse; laboratory rat; monocyte chemoattractant protein 1; protein protein interaction; renal ischemia /hypoxia

DESCRIPTION (provided by applicant): Angiotensin II (Angll) is a key regulator of blood pressure and renal function. Abnormalities in the regulation of Angll lead to hypertension (HTN) and chronic renal insufficiency (CRI), and therapies that block Angll are among the most effective in treating HTN and in delaying progression of CRI; indeed, the injurious effects of Angll now receive more attention than its physiological role. However, a limitation in our understanding of the mechanisms by which Angll exacerbate HTN and CRI arises from the fact that much of our knowledge is derived from studies that utilize pressor doses of Angll, in which Angll levels are many-fold higher than that seen in clinical scenarios. In the current proposal, we employ the chronic administration of sub-pressor doses of Angll (SP-Angll) which, while increasing intrarenal Angll levels, maintains circulating Angll within physiologic limits. SP-Angll is characterized by oxidant-dependent increases in renal vascular reactivity, blunting of salt-induced cortical hyperemia, and attendant salt-sensitive HTN; additionally, SP-Angll upregulates inflammatory chemokines (i.e. monocyte chemoattractant protein-1; MCP-1) which promote renal injury. However, SP-Angll also induces adaptive pathways (heme oxygenase-1; HO-1) which mitigate the deleterious effects of Angll, and in this regard, we recently found that SP-Angll-induced HO-1 conferred an unexpected acquired resistance to acute renal ischemic injury. Our overall goal is to uncover the mechanisms by which interactions between SP-Angll-induced MCP-1 /HO-1 determine the divergent effects of SP-Angll on acute and chronic renal injury, and salt-sensitive HTN. We propose 3 aims. In AIM #1 we will test the hypothesis that SP-Angll upregulates MCP-1, which in turn modulates renal vascular function and causes salt-sensitivity. In AIM #2 we will assess the interactions between MCP-1 and HO-1 in determining progression of chronic renal injury induced by SP-Angll, and their modulation by salt intake. In AIM #3 we will examine the cellular and hemodynamic mechanisms by which SP-Angll induces acquired resistance to acute renal failure, with emphasis on HO-1-dependent pathways. In summary, this application addresses how a specific hormone, Angll, can influence the course of three distinct, but related common illnesses: HTN, CRI and acute renal failure. Specifically, we investigate the mechanisms by which Angll initiates inflammatory cascades (that promote HTN and CRI), while simultaneously generating factors that protect against acute injury. Understanding such mechanisms, may help uncover novel therapeutic strategies in the treatment of these disorders, the importance of which is underscored by the enormous medical and financial burden that these ailments impose on the healthcare system.

描述（由申请人提供）：血管紧张素II（ANGLL）是血压和肾功能的关键调节剂。调节的异常导致高血压（HTN）和慢性肾功能不全（CRI），以及阻断Angll的疗法是治疗HTN和延迟CRI进展方面最有效的疗法之一；确实，Angll的有害影响比其生理角色更受关注。但是，我们对Angll加剧HTN和CRI的机制的理解的局限性来自于这样一个事实，即我们的许多知识源自利用Angll施加剂量的研究，其中Angll水平比临床场景中的Angll水平高得多。在当前的提案中，我们采用了长期给予亚压剂量Angll（SP-ANGLL）的施用，尽管该剂量增加了肾内ANGLL水平，但在生理限制内仍保持循环ANGLL。 Sp-Angll的特征是肾血管反应性的氧化剂依赖性增加，盐诱导的皮质充血的钝化和随之而来的盐敏感HTN。此外，SP-ANGLL上调炎症趋化因子（即单核细胞趋化蛋白-1; MCP-1），促进肾脏损伤。然而，SP-Angll还诱导了减轻Angll的有害作用的适应性途径（血红素氧酶-1; HO-1），在这方面，我们最近发现SP-Angll诱导的HO-1赋予了意外获得的对急性肾脏缺血性损伤的耐药性。我们的总体目标是揭示SP-Angll诱导的MCP-1 /HO-1之间的相互作用确定SP-ANGLL对急性和慢性肾脏损伤以及对盐敏感HTN的不同作用的机制。我们提出了3个目标。在AIM＃1中，我们将测试SP-ANGLL上调MCP-1的假设，该假设又调节了肾血管功能并引起盐敏感性。在AIM＃2中，我们将评估MCP-1和HO-1之间的相互作用，以确定SP-ANGLL诱导的慢性肾损伤的进展以及它们通过盐摄入的调节。在AIM＃3中，我们将检查SP-ANGLL诱导对急性肾衰竭的耐药性的细胞和血液动力学机制，重点是HO-1依赖性途径。总而言之，该应用程序解决了特定的激素Angll如何影响三种不同但相关的常见疾病的过程：HTN，CRI和急性肾衰竭。具体而言，我们研究了Angll启动炎症级联反应（促进HTN和CRI）的机制，同时产生了预防急性损伤的因素。了解这种机制，可能有助于发现这些疾病治疗的新型治疗策略，其重要性是由于这些疾病对医疗保健系统施加的巨大医疗和经济负担所强调的。