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.
Our studies are designed to lay the groundwork for novel therapeutic approaches for the prevention of acute kidney injury (AKI) in surgical patients or patients requiring intensive care treatment. Our preliminary studies provide compelling evidence that proton pump inhibitors could be used as a novel therapeutics for the prevention of ischemic AKI. We believe these studies are highly significant for the treatment of surgical patients suffering from AKI, as proton pump inhibitors are frequently given to surgical patients and have a great safety record. If successful, our findings could be readily translated into the clinical treatment of perioperative AKI.
|Kork, Felix; Eltzschig, Holger K (2017) The Devil Is in the Detail: Remote Ischemic Preconditioning for Perioperative Kidney Protection. Anesthesiology 126:763-765|
|Hoegl, Sandra; Ehrentraut, Heidi; Brodsky, Kelley S et al. (2017) NK cells regulate CXCR2+ neutrophil recruitment during acute lung injury. J Leukoc Biol 101:471-480|
|Neudecker, Viola; Haneklaus, Moritz; Jensen, Owen et al. (2017) Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome. J Exp Med 214:1737-1752|
|Varadarajan, Supraja G; Kong, Jennifer H; Phan, Keith D et al. (2017) Netrin1 Produced by Neural Progenitors, Not Floor Plate Cells, Is Required for Axon Guidance in the Spinal Cord. Neuron 94:790-799.e3|
|Garcia-Morales, Luis J; Chen, Ning-Yuan; Weng, Tingting et al. (2016) Altered Hypoxic-Adenosine Axis and Metabolism in Group III Pulmonary Hypertension. Am J Respir Cell Mol Biol 54:574-83|
|Luo, Renna; Liu, Chen; Elliott, Serra E et al. (2016) Transglutaminase is a Critical Link Between Inflammation and Hypertension. J Am Heart Assoc 5:|
|Baudiß, Kristin; de Paula Vieira, Rodolfo; Cicko, Sanja et al. (2016) C1P Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Preventing NF-?B Activation in Neutrophils. J Immunol 196:2319-26|
|Dehn, Shirley; DeBerge, Matthew; Yeap, Xin-Yi et al. (2016) HIF-2? in Resting Macrophages Tempers Mitochondrial Reactive Oxygen Species To Selectively Repress MARCO-Dependent Phagocytosis. J Immunol 197:3639-3649|
|Ferrari, Davide; McNamee, Eóin N; Idzko, Marco et al. (2016) Purinergic Signaling During Immune Cell Trafficking. Trends Immunol 37:399-411|
|Luo, Fayong; Le, Ngoc-Bao; Mills, Tingting et al. (2016) Extracellular adenosine levels are associated with the progression and exacerbation of pulmonary fibrosis. FASEB J 30:874-83|
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