Afferent arteriolar function and novel small molecules for renal radiation injury

描述(由申请人提供)： 放射性肾病发生在癌症的放射治疗后，也可能发生在意外或交战的辐射事件之后。因此，它与患有癌症的退伍军人和那些因军事职业暴露而遭受辐射伤害的退伍军人高度相关。目前的治疗方法是不够的。我们将测试环氧二十碳三烯酸(EET)类似物作为新的缓解剂和放射性肾病的治疗。放射性肾病导致内皮损伤，导致高血压、实质细胞丢失和肾功能衰竭。我们已经开发了具有内皮保护、抗高血压和抗细胞凋亡作用的环氧二十碳三烯酸(EET)类似物/模拟物，这些作用在这类患者中将特别有益。我们已经证明了EET类似物在高血压大鼠和代谢综合征小鼠模型中扩张肾小动脉和降低血压。我们还表明，这些新的EET类似物可以保护肾脏免受顺铂引起的肾毒性和高血压肾损伤。我们设计、合成和筛选了一系列~50个EET类似物，发现了两个新的EET类似物，它们在口服时起作用。血管松弛测定的EC50为1.5M，最大反应为14，15-EET的95%。目前治疗放射性肾病的“金标准”是血管紧张素转换酶(ACE)抑制剂卡托普利。它的好处是不完整的。需要更好的药物来治疗肾脏和其他正常组织辐射损伤。我们的中心假设是，EETs具有血管保护活性，这将转化为治疗放射性肾病的新方法。这项应用的总体目标是确定EETs在辐射诱导的传入小动脉内皮功能障碍中的作用，并在放射性肾病的动物模型中检验增加EETs将减少血管和肾脏损伤的概念。我们的长期目标是建立口服EET类似物，作为放射性肾病、其他正常组织放射性损伤以及任何涉及小动脉损伤的心血管疾病的临床治疗方法。我们将通过追求以下具体目标来验证我们的中心假设：目的1：确定辐射后传入小动脉功能障碍的时间进程和EETS的调节我们假设在放射性肾病动物模型中，EETS降低导致的传入小动脉功能障碍先于肾损伤。目的2：确定EET类似物减轻和治疗放射性肾损伤的能力。我们推测EET类似物通过抗细胞凋亡活性改善传入小动脉功能，降低血压，减轻和治疗放射性肾损伤。我们目标的实现将产生重要的积极影响，因为这将是理解辐射后肾损伤的时间进程和机制的重大进步。这些研究的结果将具有重要意义，因为它们将推动EET类似疗法的开发，用于缓解和治疗放射性肾病、其他正常组织辐射损伤以及任何涉及小动脉损伤的心血管疾病。

DESCRIPTION (provided by applicant): Radiation nephropathy occurs after radiation therapies for cancer, and may also occur after accidental or belligerent radiation events. It is thus highly relevant to veterans with cancer and o those who had radiation injury from military occupational exposures. Current treatments are insufficient. We will test epoxyeicosatrienoic acid (EET) analogues as novel mitigators and treatment of radiation nephropathy. Radiation nephropathy causes endothelial injury, results in hypertension, parenchymal cell loss, and renal failure. We have developed epoxyeicosatrienoic acid (EET) analogs/mimetics that have endothelial-protective, anti-hypertensive, and anti-apoptotic actions that will be particularly beneficial in this patient population. We have shown that an EET analog dilates renal arterioles and lowers blood pressure in hypertensive rats and a mouse model of metabolic syndrome. We have also shown that these novel EET analogs protect the kidney from cisplatin-induced nephrotoxicity and hypertensive renal injury. We designed, synthesized, and screened a series of ~50 EET analogs and found two novel EET analogs that act when given orally. Vascular relaxation determined a ~1.5 M EC50 and a maximal response that was ~95% of that of 14,15-EET. The existing "gold standard" mitigator and treatment for radiation nephropathy is captopril, an angiotensin-converting-enzyme (ACE) inhibitor. Its benefit is incomplete. Better agents are needed for renal and other normal tissue radiation injuries. Our central hypothesis is that EETs have vascular protective activities that wil translate into a novel therapeutic for radiation nephropathy. The overall objective of this application is to determine the contribution of EETs to irradiation induced afferent arteriolar endothelial dysfunction and test the concept that increasing EETs will decrease vascular and kidney injury in an animal model of radiation nephropathy. Our long-term goal is establish orally available EET analogs as clinical treatments for radiation nephropathy, other normal tissue radiation injuries, and any cardiovascular disease involving arteriolar injury. We will test our central hypothesis by pursuing the following specific aims: Aim 1: Determine the time course of afferent arteriolar dysfunction and regulation of EETs following irradiation We hypothesize that afferent arteriolar dysfunction caused by decreased EETs precedes renal injury in an animal model of radiation nephropathy. Aim 2: Determine EET analogs ability to mitigate and treat radiation-induced renal injury We hypothesize that EET analogs will improve afferent arteriolar function through anti-apoptotic activity, will decrease blood pressure and will mitigate and treat radiation induced renal injury. Achievement of our aims will have an important positive impact because these will be a significant advance towards understanding the time course for and mechanism of renal injury following irradiation. The findings of these studies will be significant because they will advance the development of EET analog therapies for the mitigation and treatment of radiation nephropathy, other normal tissue radiation injuries, and any cardiovascular disease involving arteriolar injury.