Proton Pump Inhibitors for Perioperative Acute Kidney Injury

描述（由申请方提供）：本研究提案的主要目标是确定细胞氧传感机制通过脯氨酰羟化酶（PHD 1 -3）1对急性肾损伤（阿基）的肾脏保护的功能贡献。阿基是发病率和死亡率的主要原因，迫切需要新的治疗选择2。肾缺血是AKI 3的一个非常常见的原因。因此，我们建立了肾缺血的小鼠模型以诱导AKI 4 -7。该模型使我们能够研究药理学或遗传学方法，以确定阿基的新治疗形式。在肾缺血期间，代谢供需比的变化-特别是氧气-导致严重的组织缺氧。细胞对缺氧的反应由酶调节，所述酶感测细胞氧水平并协调对缺氧或缺血的转录反应。这些酶中的核心是三种氧敏感脯氨酰羟化酶（PHD 1 -3）。有限的氧可用性导致PHD的抑制，随后稳定缺氧诱导因子（HIF）。HIF的激活驱动转录反应，该转录反应将细胞代谢转向低氧适应和存活。因此，我们假设PHDs的基因缺失或药理学抑制介导了缺血对肾脏的保护。为了实现这一假设，我们将Phd 1、Phd 2或Phd 3的基因靶向小鼠暴露于阿基，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Phd 1-/-小鼠中发现了一种选择性表型，对缺血性阿基具有显着的保护作用。为了深入了解Phd 1缺失如何保护肾脏免受缺血，我们进行了微阵列研究。基因表达的最深刻的差异是超过10倍的抑制Atp 4a，当比较缺血性肾脏Phd 1-/-小鼠与对照组。随后的ATP 4A抑制剂药理学研究模拟了Phd 1-/-小鼠中观察到的肾脏缺血保护作用，并强调了ATP 4A抑制剂在缺血性阿基期间保存肾脏能量水平的新功能。因此，我们将利用组织特异性Phd 1缺失（Aim 1）的小鼠，确定肾上皮中表达的PHD 1对肾脏保护免受阿基的贡献。我们将继续剖析HIF在缺血期间PHD介导的ATP 4A抑制中的作用（目的2），并最终研究ATP 4a缺失/抑制在肾保护免受阿基中的功能后果（目的3）。我们相信这些研究对于缺血性阿基患者的治疗具有重要意义。PHD抑制剂和质子泵抑制剂（例如埃索美拉唑）在临床上用于治疗胃酸反流。它们有效地抑制肾脏ATP 4A，并具有很好的安全性。如果成功的话，我们的研究结果可以很容易地转化为阿基的临床治疗。

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.