Supressor ANGII Determines Acute & Chronic Renal Injury

ANGII 抑制剂决定急性

• 批准号: 7624278
• 负责人: LUIS A. JUNCOS
• 金额: $ 28.87万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 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/7624278
• 关键词: Abbreviations; Accounting; Acute; Acute Kidney Failure; Address; Angiotensin II; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Arts; Attention; Blood Pressure; CCL2 gene; Chronic; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Clinical Research; Data; Disease; Dose; Enzymes; Experimental Models; Generations; Goals; Hand; Healthcare Systems; Hormones; Hyperemia; Hypertension; Inflammatory; Injury; Ischemia; Ischemic Preconditioning; Kidney; Knowledge; Laboratories; Lead; Medical; Modeling; Monocyte Chemoattractant Protein-1; Oxidants; Oxidative Stress; Pathway interactions; Physiological; Plethysmography; Property; Regulation; Renal Hypertension; Renal function; Renin; Reperfusion Therapy; Research Personnel; Resistance; Role; Sodium Chloride; Sodium-Restricted Diet; Tail; Testing; arteriole; base; catalyst; chemokine; clinically relevant; density; heme a; heme oxygenase-1; hemodynamics; inhibitor/antagonist; insight; interest; kidney vascular structure; novel therapeutics; programs; research study; salt intake; salt sensitive

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（AngII）是血压和肾功能的关键调节剂。AngII调节的异常导致高血压（HTN）和慢性肾功能不全（CRI），并且阻断AngII的疗法是治疗HTN和延迟CRI进展的最有效疗法之一;实际上，AngII的损伤作用现在比其生理作用受到更多关注。然而，我们对AngII加剧HTN和CRI的机制的理解的局限性来自于这样的事实，即我们的大部分知识来源于利用升压剂量的AngII的研究，其中AngII水平比临床情况中所见的高许多倍。在当前的提议中，我们采用长期施用降压剂量的AngII（SP-AngII），其在增加肾内AngII水平的同时，将循环AngII维持在生理限度内。SP-AngII的特征在于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伴随的盐敏感性HTN;另外，SP-AngII上调促进肾损伤的炎性趋化因子（即单核细胞趋化蛋白-1; MCP-1）。然而，SP-AngII还诱导适应性途径（血红素加氧酶-1; HO-1），其减轻AngII的有害作用，并且在这方面，我们最近发现SP-AngII诱导的HO-1赋予对急性肾缺血性损伤的意外获得性抗性。我们的总体目标是揭示SP-AngII诱导的MCP-1 /HO-1之间的相互作用决定SP-AngII对急性和慢性肾损伤以及盐敏感性HTN的不同作用的机制。我们提出三个目标。在AIM#1中，我们将测试SP-AngII上调MCP-1，其进而调节肾血管功能并引起盐敏感性的假设。在AIM #2中，我们将评估MCP-1和HO-1之间在确定由SP-AngII诱导的慢性肾损伤的进展中的相互作用，以及它们通过盐摄入的调节。在AIM #3中，我们将研究SP-AngII诱导对急性肾衰竭的获得性抵抗的细胞和血液动力学机制，重点是HO-1依赖性途径。总之，本申请解决了特定激素AngII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。具体来说，我们研究了AngII启动炎症级联反应（促进HTN和CRI）的机制，同时产生保护免受急性损伤的因子。了解这些机制可能有助于发现治疗这些疾病的新治疗策略，这些疾病对医疗保健系统造成的巨大医疗和经济负担强调了其重要性。