The kidney play a central role in the control of body fluid and composition. The cytochrome P450 (P450)- dependent arachidonic acid (AA) monooxygenase is now recognized as a component of the biomedically important AA cascade. Abundant literature data implicate P450-derived eicosanoids in various aspects of kidney function, as well as in the pathophysiology of experimental hypertension. However, the mostly descriptive nature of these studies and a paucity of appropriate experimental tools has precluded unequivocal assignments of specific functions and/or mechanisms of action to the P450 eicosanoids, as well as current on progress in the characterization of kidney P450s, to offer an integrated molecular, biochemical, biophysical and functional approach to the delineation of the physiological and/or pathophysiological significance of the renal AA monooxygenase. Metabolites, isoform specific inhibitors, cloned cDNAs and/or genes, and recombinant DNA methods will be utilized for the molecular characterization of P450-isoform specific phenotypes at the cellular, organ and whole animal levels. Functional studies will include: a) biochemical documentation of P450 isoform specific changes in cell or whole animal AA metabolism b) characterization of cellular phenotypes including hormonal responses, signaling mechanisms and ion flux and channel effects, c) the identification and characterization of hemodynamic and/or tubular effects, and d) the use of mice strains with mutated P450 genes for the integration of gene specific cell and/or organ phenotypes into whole animal physiology and/or pathophysiology. The long term goals of this project are to provide a molecular understanding of renal P450 eicosanoid biological significance and mode of action. The answer to these important questions are needed for the development of meaningful approaches to: a) the unequivocal definition of their pathophysiological significance, and b) subsequent pharmacological and/or clinical interventions.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O3))
Program Officer
Rys-Sikora, Krystyna E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Elijovich, Fernando; Milne, Ginger L; Brown, Nancy J et al. (2018) Two Pools of Epoxyeicosatrienoic Acids in Humans: Alterations in Salt-Sensitive Normotensive Subjects. Hypertension 71:346-355
Sausville, Lindsay N; Gangadhariah, Mahesha H; Chiusa, Manuel et al. (2018) The Cytochrome P450 Slow Metabolizers CYP2C9*2 and CYP2C9*3 Directly Regulate Tumorigenesis via Reduced Epoxyeicosatrienoic Acid Production. Cancer Res 78:4865-4877
Garcia, Victor; Gilani, Ankit; Shkolnik, Brian et al. (2017) 20-HETE Signals Through G-Protein-Coupled Receptor GPR75 (Gq) to Affect Vascular Function and Trigger Hypertension. Circ Res 120:1776-1788
Guo, Zhijun; Sevrioukova, Irina F; Denisov, Ilia G et al. (2017) Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria. Cell Chem Biol 24:1259-1275.e6
Zhang, Hui; Falck, John R; Roman, Richard J et al. (2017) Upregulation of 20-HETE Synthetic Cytochrome P450 Isoforms by Oxygen-Glucose Deprivation in Cortical Neurons. Cell Mol Neurobiol 37:1279-1286
Gangadhariah, Mahesha H; Dieckmann, Blake W; Lantier, Louise et al. (2017) Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia 60:1066-1075
Shuey, Megan M; Billings 4th, Frederic T; Wei, Shouzou et al. (2017) Association of gain-of-function EPHX2 polymorphism Lys55Arg with acute kidney injury following cardiac surgery. PLoS One 12:e0175292
Fan, Fan; Pabbidi, Mallikarjuna R; Ge, Ying et al. (2017) Knockdown of Add3 impairs the myogenic response of renal afferent arterioles and middle cerebral arteries. Am J Physiol Renal Physiol 312:F971-F981
Chen, Li; Joseph, Gregory; Zhang, Frank F et al. (2016) 20-HETE contributes to ischemia-induced angiogenesis. Vascul Pharmacol 83:57-65
Chiba, Takuto; Skrypnyk, Nataliya I; Skvarca, Lauren Brilli et al. (2016) Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI. J Am Soc Nephrol 27:495-508

Showing the most recent 10 out of 376 publications