Targeting oxidative stress modifiers in acute kidney injury

Summary

Principal Investigator: Sekhar P Reddy
Abstract: DESCRIPTION (provided by applicant): Acute kidney injury (AKI) caused either by ischemia reperfusion (IR) or by a nephrotoxin is common in hospitalized patients and is associated with an overall mortality rate of up to 50% in the ICU, Despite the high incidence and high mortality rate, there is no specific treatment and the pathophysiology is incompletely understood. Emerging evidence suggests that an antioxidant and oxidant imbalance (or oxidative stress) leading to cell injury, inflammatory, and immune responses participates in the pathogenesis of AKI. Thus, identifying and understanding the functions and regulation of molecular effectors that regulate oxidative stress in response to ischemic and nephrotoxic insults could lead to novel therapeutic opportunities in AKI. In preliminary studies, we found that mice with genetic disruption of Nrf2 (a b-ZIP transcription factor critical for the induction of several antioxidant and cytoprotective gene expression) are more susceptible to IRI-induced vascular permeability and inflammatory responses, as compared with wild type (Nrf2+/+) mice. Nrf2-deficient (Nrf2-/-) mice were also more susceptible to cisplatin-induced nephrotoxic AKI as compared to wild type controls. Antioxidant supplementation significantly improved renal function and histology in Nrf2-/- mice. Based on these preliminary data, we hypothesize that endogenous Nrf2 confers protection in AKI and augmentation of Nrf2 activity is a potential protective strategy for both ischemic and nephrotoxic AKI. As the translocation of Nrf2 from the cytoplasm to the nucleus is critical for ARE- mediated transcriptional response following stressful stimuli, we propose that perturbation in either specific signaling or factors controlling the Nrf2 expression and activation can result in lower levels of antioxidant enzyme expression, thereby contributing to and/or enhancing suscepitibility to the development of AKI. To test these hypotheses, we propose the following three specific aims: 1) Elucidate molecular mechanisms (upstream signals) that control the activation of Nrf2 in response to ischemia reperfusion, 2) Define the contribution of oxidative stress elicited by infiltrating leukocytes compared to resident kidney cells in the development and/or perpetuation of AKI using gene targeted Nrf2 mice, and 3) Determine whether boosting Nrf2 activation using a pharmacologic and a genetic approach confers protection against AKI. Our overall findings obtained from genetically manipulated mouse models and cell culture studies should yield extremely important insights underlying AKI and could have important implications to identify the effector mechanisms causing susceptibility to AKI. The application is developed in a multidisciplinary team approach combining strengths in transcriptional biology, in vitro and in vivo AKI models, and inflammation.
Funding Period: 2010-06-01 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. ncbi The Nrf2 triterpenoid activator, CDDO-imidazolide, protects kidneys from ischemia-reperfusion injury in mice
    Manchang Liu
    Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
    Kidney Int 85:134-41. 2014

Research Grants

  1. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
  2. Meprin A Metalloproteinase in Acute Kidney Injury
    GUR PRASAD KAUSHAL; Fiscal Year: 2013
  3. Sphingolipids in Acute Kidney Injury
    MARK DOUGLAS OKUSA; Fiscal Year: 2013
  4. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
  5. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
  6. Preclinical evaluation of resveratrol in sepsis-induced renal injury
    JOSEPH HUNTER HOLTHOFF; Fiscal Year: 2013
  7. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
  8. Retinoid Mediated Protection Against Reactive Oxygen Species Induced Cytotoxicity
    Serrine S Lau; Fiscal Year: 2013
  9. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
  10. KIDNEY INJURY MOLECULE-1 IN EPITHELIAL REPAIR
    JOSEPH VINCENT BONVENTRE; Fiscal Year: 2013

Detail Information

Publications1

  1. ncbi The Nrf2 triterpenoid activator, CDDO-imidazolide, protects kidneys from ischemia-reperfusion injury in mice
    Manchang Liu
    Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
    Kidney Int 85:134-41. 2014
    ..Thus, activation of Nrf2 signaling with CDDO-imidazolide confers protection from AKI, and presents a new therapeutic opportunity for this common and serious condition. ..

Research Grants30

  1. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  2. Meprin A Metalloproteinase in Acute Kidney Injury
    GUR PRASAD KAUSHAL; Fiscal Year: 2013
    ..The studies proposed in this application are aimed directly at understanding these mechanisms, which will result in appropriate therapeutic interventions. ..
  3. Sphingolipids in Acute Kidney Injury
    MARK DOUGLAS OKUSA; Fiscal Year: 2013
    ..Our studies will identify new pathways that participate in early injury associated with AKI and identify targets for therapeutic intervention using new S1PR- directed compounds. ..
  4. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  5. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  6. Preclinical evaluation of resveratrol in sepsis-induced renal injury
    JOSEPH HUNTER HOLTHOFF; Fiscal Year: 2013
    ..This proposal investigates new therapeutic targets to treat sepsis and has the potential to identify new agents to reduce mortality of this devastating condition. ..
  7. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  8. Retinoid Mediated Protection Against Reactive Oxygen Species Induced Cytotoxicity
    Serrine S Lau; Fiscal Year: 2013
    ....
  9. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  10. KIDNEY INJURY MOLECULE-1 IN EPITHELIAL REPAIR
    JOSEPH VINCENT BONVENTRE; Fiscal Year: 2013
    ....
  11. Novel endonuclease-targeted approaches to nephroprotection
    Alexei G Basnakian; Fiscal Year: 2013
    ..This proposal will likely result in new therapies, and may eventually allow saving human lives, improving the health of veterans, and decreasing the number of disabilities in the veteran population. ..