Proton Pump Inhibitors for Perioperative Acute Kidney Injury

描述(由申请人提供)：本研究计划的主要目的是确定细胞氧感应机制对急性肾损伤(AKI)肾脏保护的功能贡献。急性心肌梗死是发病率和死亡率的主要原因，迫切需要新的治疗方案2。肾缺血是AKI3非常常见的原因。因此，我们建立了一种小鼠肾缺血模型，以诱导AKI4-7。这个模型允许我们检查药理学或遗传学方法，以确定AKI的新治疗形式。在肾脏缺血期间，代谢供需比的变化-特别是氧气-导致严重的组织缺氧。细胞对缺氧的反应是由感受细胞氧水平并协调对缺氧或缺血的转录反应的酶来调节的。这些酶中的中心是三个氧感应脯氨酸羟基酶(Phd1-3)。有限的氧气供应导致PHDS的抑制，随后缺氧诱导因子(HIF)的稳定。HIFs的激活驱动转录反应，引导细胞代谢朝着低氧适应和生存方向发展。因此，我们假设PHD的基因缺失或药物抑制介导了肾脏缺血保护。为了进一步研究这一假说，我们将PhD1、PHD2或PHD3基因定位的小鼠暴露于AKI中，并通过测量肾小球滤过率或组织学来评估肾功能。令人惊讶的是，我们在PhD1-/-小鼠中发现了一种选择性表型，对缺血性AKI具有显著的保护作用。为了从机制上深入了解PhD1缺失如何保护肾脏免受缺血，我们进行了微阵列研究。当比较phd1-/-小鼠和对照组的缺血肾脏时，基因表达的最大差异是Atp4a的抑制超过10倍。随后对药物ATP4A抑制剂的研究模仿了在PhD1-/-小鼠中看到的肾脏缺血保护作用，并强调了ATP4A抑制剂在缺血性AKI期间保存肾脏能量水平的新功能。因此，我们将利用Tsue特异性PhD1缺失的小鼠(Aim1)来确定肾上皮细胞中表达的PhD1在AKI肾脏保护中的作用。我们将继续剖析HIFs在PhD介导的ATP4A在缺血期间抑制中的作用(目标2)，最后研究Atp4a缺失/抑制在AKI肾脏保护中的功能后果(目标3)。我们相信这些研究对于治疗缺血性AKI患者具有重要意义。PHD抑制剂和质子泵抑制剂(例如埃索美拉唑)在临床上用于治疗酸反流。它们有效地抑制肾脏ATP4A，并具有很大的安全性。如果成功，我们的发现可以很容易地转化为AKI的临床治疗。

DESCRIPTION (provided by applicant): The main goal of this research proposal is to identify the functional contribution of cellular oxygen sensing mechanisms through prolylhydroxylases (PHD1-3)1 to renal protection from acute kidney injury (AKI). AKI is a leading cause of morbidity and mortality and novel treatment options are urgently needed2. Renal ischemia is a very common cause of AKI3. Therefore, we established a murine model of renal ischemia to induce AKI4-7. This model allows us to examine pharmacologic or genetic approaches to identify novel treatment forms for AKI.During renal ischemia, shifts in the metabolic supply and demand ratio - particularly for oxygen - result in severe tissue hypoxia. Cellular responses to hypoxia are regulated by enzymes that sense cellular oxygen levels and coordinate transcriptional responses to hypoxia or ischemia. Central among these enzymes are three oxygen sensing prolyl hydroxylases (PHD1-3). Limited oxygen availability results in inhibition of PHDs with subsequent stabilization of hypoxia-inducible factors (HIFs). Activation of HIFs drives a transcriptional response that steers cellular metabolism towards hypoxia adaptation and survival. Thus, we hypothesized that genetic deletion or pharmacologic inhibition of PHDs mediates kidney protection from ischemia. To pursue this hypothesis, we exposed gene-targeted mice for Phd1, Phd2 or Phd3 to AKI and assessed renal function by measuring GFR or histology. Surprisingly, we found a selective phenotype in Phd1-/- mice with remarkable protection from ischemic AKI. To gain mechanistic insight into how Phd1 deletion protects the kidneys from ischemia, we performed microarray studies. The most profound difference in gene expression was an over 10 fold repression of Atp4a, when comparing ischemic kidneys from Phd1-/- mice with controls. Subsequent studies with pharmacologic ATP4A inhibitors mimicked the kidney protection from ischemia seen in Phd1-/- mice, and highlight a novel function for ATP4A inhibitors in conserving renal energy levels during ischemic AKI. Therefore, we will define the contribution of PHD1 expressed in renal epithelia to kidney protection from AKI, utilizing mice with tisue specific Phd1 deletion (Aim1). We will go on to dissect the role of HIFs in PHD- mediated ATP4A repression during ischemia (Aim 2), and finally study functional consequences of Atp4a deletion/inhibition in kidney protection from AKI (Aim 3). We believe these studies are highly significant for the treatment of patients suffering from ischemic AKI. PHD inhibitors and inhibitors for proton pumps (e.g. esomeprazole) are used clinically for the treatment of acid reflux. They efficiently inhibit renal ATP4A and have a great safety profile. If successful, our findings could be readily translated into the clinical treatment of AKI.