Acute kidney injury (AKI) is an untreatable, frequently lethal malady which is common in the critically ill. AKI is more common and more severe in men than women, suggesting sex represents an opportunity for intervention. Investigation of AKI has recently highlighted endothelial cells. Estrogen is an endothelial protectant. This proposal tests the hypothesis that females are protected from AKI in part because estrogen protects renal endothelium, preserving overall renal function.
Aim 1 will determine whether glomerular endothelial and renal functional injury after cardiac arrest and cardiopulmonary resuscitation (CA/CPR) is sexually dimorphic and mediated by estrogen. The hypothesis to be tested is that estrogen protects glomerular and tubular function in both sexes after CA/CPR.
Aim 2 will focus on molecular mechanisms. The hypothesis to be tested is that estrogen attenuates glomerular endothelial functional changes which may damage proximal tubular epithelial cells.
Aim 3 will use molecular ultrasound to evaluate the findings of aim 2 in an in vivo model. The hypothesis to be tested is that female renoprotection from CA/CPR occurs because estrogen augments renal endothelial integrity. These hypotheses will be tested using an in vivo mouse model of CA/CPR in which mice undergo 10 minutes of CA followed by CPR. Renal outcomes are assessed at multiple time points in aim 1.
Aim 2 will be conducted in an in vitro model, using mouse glomerular endothelial cells and mouse proximal tubular epithelial cells. Gomerular endothelial cells are exposed to oxygen/glucose deprivation, in combination with estrogen, estrogen receptor antagonists, and related agents. Glomerular endothelial permeability and the effect of oxygen-glucose deprived glomerular endothelial cells on tubular epithelial cells will be assessed.
Aim 3 will use molecular ultrasound with antibody-tagged microbubble contrast to assess renal endothelium in post-CA/CPR mice. Our preliminary data indicate that estrogen is renoprotective after CA/CPR, and that this may be through the G protein-coupled estrogen receptor GPRR30. We have also shown that glomerular endothelial permeability is altered after CA/CPR, and that these cells are protected by estrogen in vitro. AKI is extremely common in critically ill patients and has up to 70% mortality. This research is based on the observation that females are less affected. Significant research has been performed on AKI without meaningful change in outcome, but this novel research offers a new approach.

Public Health Relevance

Acute kidney injury (AKI) is an untreatable, common and severe condition which occurs in critically ill patients. Women are protected from AKI, and in animal studies, estrogen may be protective. The proposed work aims to evaluate mechanisms of estrogen's protective action with the hope of offering possibilities for treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK090754-03
Application #
8464084
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2011-07-15
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$151,238
Indirect Cost
$11,203
Name
Oregon Health and Science University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Wakasaki, Rumie; Eiwaz, Mahaba; McClellan, Nicholas et al. (2018) Automated systematic random sampling and Cavalieri stereology of histologic sections demonstrating acute tubular necrosis after cardiac arrest and cardiopulmonary resuscitation in the mouse. Histol Histopathol 33:1227-1234
Yockelson, Shaun R; Heitner, Stephen B; Click, Sarah et al. (2018) Right Ventricular Systolic Performance Determined by 2D Speckle-Tracking Echocardiography and Acute Kidney Injury After Cardiac Surgery. J Cardiothorac Vasc Anesth :
Schenning, Katie J; Casson, Henry; Click, Sarah V et al. (2017) Vapor Pressures of Anesthetic Agents at Temperatures Below 0°C and a Novel Anesthetic Delivery Device. Anesth Analg 124:473-479
Hall, Michael; Robertson, Jamie; Merkel, Matthias et al. (2017) A Structured Transfer of Care Process Reduces Perioperative Complications in Cardiac Surgery Patients. Anesth Analg 125:477-482
Ikeda, Mizuko; Wakasaki, Rumie; Schenning, Katie J et al. (2017) Determination of renal function and injury using near-infrared fluorimetry in experimental cardiorenal syndrome. Am J Physiol Renal Physiol 312:F629-F639
Schenning, Katie J; Anderson, Sharon; Alkayed, Nabil J et al. (2015) Hyperglycemia abolishes the protective effect of ischemic preconditioning in glomerular endothelial cells in vitro. Physiol Rep 3:
Ikeda, Mizuko; Swide, Thomas; Vayl, Alexandra et al. (2015) Estrogen administered after cardiac arrest and cardiopulmonary resuscitation ameliorates acute kidney injury in a sex- and age-specific manner. Crit Care 19:332
Hutchens, M P; Drennan, S L; Cambronne, E D (2015) Calibration of optimal use parameters for an ultraviolet light-emitting diode in eliminating bacterial contamination on needleless connectors. J Appl Microbiol 118:1298-305
Hutchens, Michael P; Fujiyoshi, Tetsuhiro; Koerner, Ines P et al. (2014) Extracranial hypothermia during cardiac arrest and cardiopulmonary resuscitation is neuroprotective in vivo. Ther Hypothermia Temp Manag 4:79-87
Kuchena, Admire; Merkel, Matthias J; Hutchens, Michael P (2014) Postcardiac arrest temperature management: infectious risks. Curr Opin Crit Care 20:507-15

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