Renal microsomal cytochrome P-450 catalyzes the in vitro and in vivo oxygenated metabolism of arachidonic acid to products that include epoxyeicosatrienoic acids (EETs), 19- and 20-hydroxyeicosatetraenoic acids (19- and 20-OH-AA). The potential significance of this branch of the arachidonate cascade to renal function has been suggested by a) the potent biological activities of some of its metabolites, b) the demonstration of endogenous, enantioselective, formation of EETs, c) the regulation of the enzymes involved and/or of its metabolites by dietary salt loading, DOCA administration or by experimental hypertension and, d) the preferential expression of the cytochrome P-450 4A2 gene in hypertensive (SHR) rats. More recently, the demonstration of EETs as endogenous constituents of human kidney and urine and their increased urinary excretion during pregnancy induced hypertension suggest that this pathway may fulfill a yet unidentified role in human kidney physiology and/or pathophysiology. As part of a multidisciplinary effort to approach experimentally these important questions and, in support of projects 1-6, Core B will apply standard and established methods of eicosanoid extraction, purification, HPLC, GC/MS, protein immunoblotting and, cDNA purification and documentation to the identification, characterization and quantification of the enzymes and the metabolites of this branch of the arachidonate cascade.

Project Start
1998-08-01
Project End
1998-11-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
12
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
Imig, J D (2016) Epoxyeicosatrienoic Acids and 20-Hydroxyeicosatetraenoic Acid on Endothelial and Vascular Function. Adv Pharmacol 77:105-41
Savas, Üzen; Wei, Shouzou; Hsu, Mei-Hui et al. (2016) 20-Hydroxyeicosatetraenoic Acid (HETE)-dependent Hypertension in Human Cytochrome P450 (CYP) 4A11 Transgenic Mice: NORMALIZATION OF BLOOD PRESSURE BY SODIUM RESTRICTION, HYDROCHLOROTHIAZIDE, OR BLOCKADE OF THE TYPE 1 ANGIOTENSIN II RECEPTOR. J Biol Chem 291:16904-19

Showing the most recent 10 out of 376 publications