Supressor ANGII Determines Acute & Chronic Renal Injury

描述（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。Angll调节异常可导致高血压（HTN）和慢性肾功能不全（CRI），阻断Angll的治疗是治疗HTN和延缓CRI进展最有效的方法之一；事实上，Angll的有害影响现在比它的生理作用受到更多的关注。然而，我们对Angll加剧HTN和CRI的机制的理解存在局限性，因为我们的大部分知识来自使用加压剂量Angll的研究，其中Angll水平比临床情况高出许多倍。在目前的建议中，我们采用亚压剂量的Angll （SP-Angll）慢性给药，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，盐诱导的皮质充血变钝，以及随之而来的盐敏感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），促进肾损伤。然而，SP-Angll也诱导适应性通路（血红素氧化酶-1；HO-1），从而减轻Angll的有害影响，在这方面，我们最近发现SP-Angll诱导的HO-1对急性肾缺血损伤具有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对急慢性肾损伤和盐敏感性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-Angll上调MCP-1的假设，MCP-1反过来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在决定SP-Angll诱导的慢性肾损伤进展中的相互作用，以及盐摄入量对它们的调节。在AIM #3中，我们将研究SP-Angll诱导急性肾衰获得性耐药的细胞和血流动力学机制，重点研究ho -1依赖性途径。总之，该应用程序解决了一种特定的激素，Angll，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）的机制，同时产生防止急性损伤的因子。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，这些疾病给医疗保健系统带来的巨大医疗和经济负担强调了其重要性。

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.