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Principal Investigator: Tomokazu Souma
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $484,168
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
Acute kidney injury (AKI) is a major health problem, afflicting 1.2 million hospitalized patients annually in the US.
Maladaptive renal repair after AKI promotes development of chronic kidney disease (CKD), leaving affected
patients at high risk for dialysis dependency, cardiovascular events, and mortality. Studies show that males are
disproportionately and more severely affected by AKI than females, including COVID-19-associated AKI.
However, the molecular mechanisms underlying this sexual dimorphism remain poorly understood. Moreover,
there are no targeted therapies that interrupt this devastating disease process in both sexes. Using single-cell
transcriptomics and mouse genetics, our ongoing studies found that the female sex confers marked protection
against ferroptosis, a distinct, non-apoptotic form of regulated cell death and a critical driver of maladaptive repair
after AKI in mice and humans. Ferroptosis is triggered by the inability of glutathione peroxidase 4 (GPX4) to
remove toxic lipid peroxides from cell membranes, leading to the accelerated accumulation of toxic lipid
peroxides (ferroptotic stress) and cell rupture. Acute ischemic and toxic kidney injuries reduce GPX4 in proximal
tubular (PT) cells, thus making these cells vulnerable to ferroptosis. Severe AKI also induces pathologic
transcriptional alteration of PT cells into an inflammatory phenotype and prevents their recovery to a healthy
state (impaired plasticity). Our data show that in males but not in females, genetic deletion of Gpx4 promotes
the accumulation of inflammatory PT cells and triggers their death by ferroptosis. To advance these clinically
impactful lines of investigation, we will test our overarching hypothesis that sexual dimorphism in resilience to
ferroptosis underlies sex differences in clinical outcomes after AKI. We further hypothesize that uncovering the
mechanisms of how sex hormones regulate ferroptosis sensitivity will enable identification of targetable
downstream pathways that improve AKI outcomes for both sexes. Directly testing these hypotheses, we will
integrate unbiased single-cell transcriptomics, genetic mouse models, pharmacological studies, and human
kidney organoids with two Specific Aims. In Aim 1, we will determine sex-dependent mechanisms by which
ferroptosis promotes maladaptive repair at single-cell resolution using our tubule-specific, doxycycline-inducible
Gpx4 knockout mouse model. We will also investigate the therapeutic effects of ferroptosis inhibitors to enhance
renal repair in our murine kidney injury models in vivo and in human in vitro AKI models using organoids. In Aim
2, we will test our hypothesis that sex hormones regulate the sensitivity to ferroptosis and PT cell plasticity after
AKI using gonadectomy and genetic inhibition of estrogen receptor signaling. The results of these studies will
provide compelling preclinical mechanistic evidence for how ferroptotic stress governs PT cell fate. Our studies
will identify new therapeutic targets to enhance renal ferroptotic stress resilience and promote healthy PT
recovery from injury, thereby interrupting the AKI to CKD transition in both sexes.
Terms: <Acceleration><Acute><Acute Renal Failure with Renal Papillary Necrosis><Affect><Attenuated><CMKRL2><COVID-19><CV-19><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Culture Techniques><Cell Death><Cell membrane><Cells><Cessation of life><Chemokine Receptor-Like 2><Chronic><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><Coronavirus Infectious Disease 2019><Cytoplasmic Membrane><Data><Death><Dependence><Development><Dialysis><Dialysis procedure><Differences between sexes><Differs between sexes><Disease><Disorder><Doxycycline><ERalpha><ERα><ESR1><ESR1 gene><Environment><Estradiol Receptor alpha><Estradiol Receptor α><Estrogen Receptor 1><Estrogen Receptor alpha><Estrogen Receptor α><Estrogen Receptors><Estrogens><Event><Exhibits><Fatty Acid Hydroperoxides><Female><Fibrosis><G Protein-Coupled Estrogen Receptor><G Protein-Coupled Receptor 30><GPER><GPER gene><GPR30><Genetic><Gonadal Steroid Hormones><Health><Heart Vascular><Histopathology><Hormonal><Hospital Admission><Hospitalization><Human><Immune><Immune response><Immunes><Immunological response><Impairment><In Vitro><Inflammation><Inflammatory><Injury to Kidney><Interruption><Investigation><Ischemia><Ischemia-Reperfusion Injury><KO mice><Kidney><Kidney Urinary System><Knock-out Mice><Knockout Mice><Knowledge><Lipid Hydroperoxide><Lipid Peroxidation><Lipid Peroxides><Lipoperoxides><Longitudinal Studies><LoxP-flanked allele><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Mutant Strains Mice><NR3A1><Null Mouse><Oophorectomy><Operative Procedures><Operative Surgical Procedures><Organ><Organoids><Outcome><Ovariectomy><Pathogenesis><Pathogenicity><Pathologic><Pathway interactions><Patients><Pharmacological Study><Pharmacology Study><Phenotype><Plasma Membrane><Predisposition><Process><Receptor Signaling><Recovery><Reduced Glutathione><Regulation><Regulatory Pathway><Renal function><Reperfusion Damage><Reperfusion Injury><Research><Residual><Residual state><Resolution><Risk><Rupture><Sex Differences><Sex Hormones><Sex Steroid Hormones><Sexual differences><Stress><Surgical><Surgical Interventions><Surgical Procedure><Susceptibility><Tamoxifen><Testing><Testosterone><Therapeutic Effect><Therapeutic Estrogen><Therapeutic Testosterone><Trans-Testosterone><Transcription Alteration><Tubular><Tubular formation><Vibramycin><acute kidney injury><alpha-6-Deoxyoxytetracycline><attenuate><attenuates><cell culture><cell cultures><chronic kidney disease><circulatory system><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><design><designing><developmental><dialysis therapy><early experience><epithelial injury><female gonadectomy><female sex hormone><floxed><floxed allele><glutathione peroxidase><gonadal steroids><high risk><host response><iPS><iPSC><iPSCs><immune system response><immunoresponse><improved><in vivo Model><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><inhibitor><injury recovery><insight><ischemia injury><ischemic injury><kidney fibrosis><kidney function><kidney injury><kidney repair><lipid peroxide><long-term study><longitudinal outcome studies><longterm study><male><mortality><mouse genetics><mouse model><mouse mutant><murine model><necrocytosis><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><pathway><pharmacologic><plasmalemma><pre-clinical><preclinical><prevent><preventing><recovery after injury><recovery following injury><recovery post injury><renal><renal fibrosis><renal injury><repair><repaired><resilience><resilient><resilient to stress><resolutions><response><sex><sex based differences><sex dimorphism><sex steroid><sex-dependent differences><sex-related differences><sex-specific differences><sexual dimorphism><sexually dimorphic><stress resilience><stress resiliency><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptomics>