Supressor ANGII Determines Acute & Chronic Renal Injury

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 调节异常会导致高血压 (HTN) 和慢性肾功能不全 (CRI)，而阻断 AngII 的疗法是治疗 HTN 和延缓 CRI 进展的最有效方法之一；事实上，Angll 的有害作用现在比其生理作用更受关注。然而，我们对 Angll 加剧 HTN 和 CRI 机制的理解存在局限性，因为我们的大部分知识都来自于利用 Angll 升压剂量的研究，其中 Angll 水平比临床情况中看到的水平高出许多倍。在当前的提案中，我们采用亚升压剂量的 Angll (SP-Angll) 长期给药，在增加肾内 Angll 水平的同时，将循环 Angll 维持在生理限度内。 SP-Angll 的特点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减弱以及随之而来的盐敏感性 HTN；此外，SP-AngII上调炎症趋化因子（即单核细胞趋化蛋白-1；MCP-1），从而促进肾损伤。然而，SP-Angll也诱导适应性途径（血红素加氧酶-1；HO-1），其减轻Angll的有害作用，在这方面，我们最近发现SP-Angll诱导的HO-1赋予对急性肾缺血性损伤的意想不到的获得性抵抗。我们的总体目标是揭示 SP-Angll 诱导的 MCP-1 /HO-1 之间的相互作用决定 SP-Angll 对急性和慢性肾损伤以及盐敏感性 HTN 的不同影响的机制。我们提出 3 个目标。在 AIM #1 中，我们将检验 SP-Angll 上调 MCP-1 的假设，MCP-1 进而调节肾血管功能并导致盐敏感性。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-AngII 诱导的慢性肾损伤的进展，以及盐摄入对它们的调节。在 AIM #3 中，我们将研究 SP-Angll 诱导获得性急性肾衰竭抵抗力的细胞和血流动力学机制，重点是 HO-1 依赖性途径。总之，该应用解决了特定激素 AngII 如何影响三种不同但相关的常见疾病的病程：HTN、CRI 和急性肾衰竭。具体来说，我们研究了 Angll 启动炎症级联反应（促进 HTN 和 CRI），同时产生防止急性损伤的因子的机制。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，这些疾病给医疗保健系统带来的巨大医疗和财政负担凸显了其重要性。

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.