Mechanisms of Renoprotection by Soluble Epoxide Hydrolase Inhibition

Summary

Principal Investigator: Deanna L Kroetz
Abstract: DESCRIPTION (provided by applicant): Soluble epoxide hydrolase (sEH) is a dual function Phase II metabolic enzyme that catalyzes the hydrolysis of both xenobiotic and endobiotic epoxides. sEH metabolism of xenobiotic epoxides often results in their detoxification and accelerated elimination, whereas that of endobiotic epoxides is generally associated with attenuation of epoxide biological properties. Endogenous substrates of sEH are unsaturated fatty acid epoxides, including epoxyeicosatrienoic acids (EETs), which are major products of cytochrome P450 (CYP)-catalyzed metabolism of arachidonic acid, an essential fatty acid nutrient. The hydrolysis of EETs to their corresponding dihydroxyeicosatrienoic acids by sEH has recently emerged as a key factor controlling the biological effects of EETs, including vasoactive, anti- inflammatory and anti-apoptotic effects. Recent preliminary data from our laboratory shows that chemical or genetic disruption of sEH activity protects against acute kidney injury induced by cisplatin treatment. Specifically, the protective effects of sEH inhibition are associated with decreased inflammation and a dramatic attenuation of apoptosis. The focus of this proposal is to understand the mechanistic basis for the renoprotection afforded by disruption of sEH activity. Three specific aims are proposed to test the overall hypothesis that inhibition of sEH protects against acute kidney injury. The first aim will identify the signaling pathways involved in the renoprotective effect of sEH inhibition in a cisplatin model of acute kidney injury. The role of NF-?B and PPAR? signaling will be examined, particularly with respect to the anti-inflammatory effects of sEH inhibition in acute kidney injury. The effect of sEH inhibition on the intrinsic mitochondrial apoptotic pathway will also be investigated. Studies proposed for the second aim will extend our findings in a cisplatin model of acute kidney injury to additional models which involve different renal insults and signaling pathways. The renoprotective properties of sEH inhibition will be studied in both a unilateral ureter ligation model and in ischemia/reperfusion. Finally, the third aim will directly test the ability of EETs to protect against drug- or ischemia-induced renal cell injury, using cultured renal epithelial cells. The relative contribution of vascular versus tubular formed fatty acid epoxides in renoprotection will also be tested, using mouse strains with tissue specific overexpression or disruption of CYP epoxygenases and sEH. A combination of chemical and genetic tools to modulate sEH activity and EET production provide the critical framework to advance our preliminary observation of renoprotection associated with sEH inhibition. A long term goal of these studies is to develop strategies for the therapeutic modulation of sEH for the prevention and treatment of acute kidney injury. The general nature of the anti-inflammatory and anti-apoptotic effects of sEH inhibition will make our findings more broadly relevant to diseases affecting other organs as well. PUBLIC HEALTH RELEVANCE: Acute kidney injury is a complex syndrome occurring in 20% to 30% of critically ill patients, and is associated with increased mortality, hospitalization, use of healthcare resources, and costs. Despite decades of research in animal models, effective strategies for prevention of acute kidney injury have yet to make it to the clinic. The studies proposed in this application will explore a novel pathway for protection against acute kidney injury which exploits an abundant renal fatty acid epoxide with established roles in inflammation and apoptosis.
Funding Period: 2010-08-01 - 2015-07-31
more information: NIH RePORT

Top Publications

  1. pmc Attenuation of cisplatin-induced renal injury by inhibition of soluble epoxide hydrolase involves nuclear factor κB signaling
    Yingmei Liu
    Department of Bioengineering, University of California, San Francisco, San Francisco, CA 94158, USA
    J Pharmacol Exp Ther 341:725-34. 2012
  2. pmc Epoxyeicosatrienoic acids prevent cisplatin-induced renal apoptosis through a p38 mitogen-activated protein kinase-regulated mitochondrial pathway
    Yingmei Liu
    Departments of Bioengineering and Therapeutic Sciences Y L, X L, S N, D L K and Anatomic Pathology J L O, University of California San Francisco, San Francisco, California and Arête Therapeutics, Hayward, California H K W
    Mol Pharmacol 84:925-34. 2013

Research Grants

  1. Biologic Effects of Cdk2 Substrate Phosphorylation on Acute Kidney Injury
    Peter M Price; Fiscal Year: 2013
  2. Targeting oxidative stress modifiers in acute kidney injury
    Sekhar P Reddy; Fiscal Year: 2013
  3. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
  4. Role of Eicosanoids in Renal Function
    NANCY JOAN BROWN; Fiscal Year: 2013
  5. MOLECULAR BIOLOGY OF HEMORRHAGIC SHOCK
    Timothy R Billiar; Fiscal Year: 2013
  6. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
  7. Cytochrome P450 Derived Eicosanoids and Inflammation
    Craig R Lee; Fiscal Year: 2013
  8. HYDROLYTIC ENZYMES IN THE METABOLISM OF TOXINS
    Bruce D Hammock; Fiscal Year: 2013
  9. Acute Kidney Injury and Double Negative T Cells
    Hamid Rabb; Fiscal Year: 2013
  10. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013

Detail Information

Publications2

  1. pmc Attenuation of cisplatin-induced renal injury by inhibition of soluble epoxide hydrolase involves nuclear factor κB signaling
    Yingmei Liu
    Department of Bioengineering, University of California, San Francisco, San Francisco, CA 94158, USA
    J Pharmacol Exp Ther 341:725-34. 2012
    ..These data suggest that EETs or other fatty acid epoxides can attenuate cisplatin-induced kidney injury and sEH inhibition is a novel renoprotective strategy...
  2. pmc Epoxyeicosatrienoic acids prevent cisplatin-induced renal apoptosis through a p38 mitogen-activated protein kinase-regulated mitochondrial pathway
    Yingmei Liu
    Departments of Bioengineering and Therapeutic Sciences Y L, X L, S N, D L K and Anatomic Pathology J L O, University of California San Francisco, San Francisco, California and Arête Therapeutics, Hayward, California H K W
    Mol Pharmacol 84:925-34. 2013
    ..Collectively, these in vivo and in vitro studies demonstrate a role for EETs in limiting cisplatin-induced renal apoptosis. Inhibition of sEH represents a novel therapeutic strategy for protection against cisplatin-induced renal damage. ..

Research Grants30

  1. Biologic Effects of Cdk2 Substrate Phosphorylation on Acute Kidney Injury
    Peter M Price; Fiscal Year: 2013
    ..Our proposal will lead to the development of agents that can be used to prevent AKI, which will directly impact patient care and well-being and which is highly relevant to veterans'health issues and to the VA mission. ..
  2. Targeting oxidative stress modifiers in acute kidney injury
    Sekhar P Reddy; Fiscal Year: 2013
    ..The application is developed in a multidisciplinary team approach combining strengths in transcriptional biology, in vitro and in vivo AKI models, and inflammation. ..
  3. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  4. Role of Eicosanoids in Renal Function
    NANCY JOAN BROWN; Fiscal Year: 2013
    ..These are needed for the development of meaningful approaches for: a) the unequivocal definition of human pathophysiological significance, and b) future pharmacological targeting, and clinical diagnosis and intervention. ..
  5. MOLECULAR BIOLOGY OF HEMORRHAGIC SHOCK
    Timothy R Billiar; Fiscal Year: 2013
    ..Based on our progress thus far, we are fully confident that our approach will continue to lead to productive collaboration and effective testing of a novel and important hypotheses. ..
  6. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  7. Cytochrome P450 Derived Eicosanoids and Inflammation
    Craig R Lee; Fiscal Year: 2013
    ..abstract_text> ..
  8. HYDROLYTIC ENZYMES IN THE METABOLISM OF TOXINS
    Bruce D Hammock; Fiscal Year: 2013
    ..This knowledge will also predict risk from environmental chemicals that increase or decrease the levels of epoxide hydrolases. ..
  9. Acute Kidney Injury and Double Negative T Cells
    Hamid Rabb; Fiscal Year: 2013
    ..We will also elucidate mechanisms of action. Results will provide novel information on this newly identified kidney cell and has the potential to harness a novel cell for cell therapy directed to ischemia reperfusion injury. ..
  10. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
    ..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..
  11. PERINATAL MECHANISMS OF DETOXIFICATION
    Eric F Johnson; Fiscal Year: 2013
    ..Additionally, we will address how genetic deficiencies of this capacity affect susceptibility to hypertension due to renal and liver dysfunction. ..
  12. 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. ..
  13. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  14. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  15. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  16. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  17. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  18. Human mesenchymal stem cell microvesicles for the treatment of acute lung injury
    Jae Woo Lee; Fiscal Year: 2013
    ..Furthermore, the results may provide preclinical data that could facilitate development of MSC MV as a therapy for ALI. ..
  19. 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. ..
  20. KIDNEY INJURY MOLECULE-1 IN EPITHELIAL REPAIR
    JOSEPH VINCENT BONVENTRE; Fiscal Year: 2013
    ....