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标是确定通过脯氨酸羟化酶（PHD1-3）1的细胞氧感应机制对急性肾损伤（AKI）肾脏保护的功能贡献。AKI是发病率和死亡率的主要原因，迫切需要新的治疗方案2。肾缺血是引起AKI3的一个非常常见的原因。因此，我们建立小鼠肾缺血模型诱导AKI4-7。该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。在肾缺血期间，代谢供需比的变化——特别是氧的变化——导致严重的组织缺氧。细胞对缺氧的反应是由酶调节的，酶能感知细胞氧水平，并协调对缺氧或缺血的转录反应。这些酶的中心是三种氧感应脯氨酸羟化酶（PHD1-3）。有限的氧气可用性导致博士抑制，随后缺氧诱导因子（hif）稳定。hif的激活驱动转录反应，引导细胞代谢向缺氧适应和生存。因此，我们假设基因缺失或药物抑制博士介导肾缺血保护。为了验证这一假设，我们将基因靶向的Phd1， Phd2或Phd3小鼠暴露于AKI中，并通过测量GFR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。为了了解Phd1缺失如何保护肾脏免受缺血的机制，我们进行了微阵列研究。当将Phd1-/-小鼠的缺血肾脏与对照进行比较时，基因表达最深刻的差异是Atp4a的抑制超过10倍。随后的药理ATP4A抑制剂研究模拟了Phd1-/-小鼠对缺血肾脏的保护作用，并强调了ATP4A抑制剂在缺血性AKI期间保护肾脏能量水平的新功能。因此，我们将利用具有组织特异性PHD1缺失（Aim1）的小鼠，确定肾上皮中PHD1表达对AKI肾脏保护的贡献。我们将继续剖析hif在缺血期间PHD介导的ATP4A抑制中的作用（目的2），并最终研究ATP4A缺失/抑制在AKI肾脏保护中的功能后果（目的3）。我们相信这些研究对缺血性AKI患者的治疗具有重要意义。博士抑制剂和质子泵抑制剂（如埃索美拉唑）在临床上用于治疗胃酸反流。它们有效地抑制肾脏ATP4A，并且具有很高的安全性。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.