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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK097075-02
Application #
8641353
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kimmel, Paul
Project Start
2013-04-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$336,672
Indirect Cost
$119,172
Name
University of Colorado Denver
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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