Sex Difference in Renal Injury After Cardiac Arrest:Mechanisms of Estrogen Action

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DESCRIPTION (provided by applicant): 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.