Overall, our long-term goal is to obtain a better understanding of the regulation of renal epoxygenase enzymes and determine the role they play in renal function. The presence of an active cytochrome P450 monooxygenase in renal tissue is well documented. Even though the kidney contains the second highest body concentration of cytochrome P450 enzymes, relatively little is known about the catalytic and molecular properties of the renal hemoproteins. In earlier studies it was shown that, in addition to catalyzing lauric acid omega/omega-1 oxidation, kidney cytochrome P450 was active in the metabolism of several drugs and carcinogens. The inducibility and the segmental distribution of specific cytochrome P450 isoforms along the nephron is well established. The initial demonstration of a role for cytochrome P450 in the omega/omega-1 oxidation of prostanoids and leukotrienes, known urinary metabolites of these functionally important mediators, suggested a physiological role for this enzyme system. More recent studies have documented a function for renal cytochrome P450 as an active catalyst for the metabolism of arachidonic acid to biologically active products.
The specific aim of this project is to isolate and characterize genes encoding cytochrome P450 2C (epoxygenase) family members from rat kidney and determine the molecular basis for the effect of dietary salt loading on this enzyme system. Preliminary evidence indicates that this family of cytochrome P450 isoforms is involved in the metabolism of endogenous substrates (arachidonic acid) to bio-active compounds which affect renal vascular tone, free water and ion transport. The enzymatic activity of one of these isoforms has been shown to be dramatically induced in the kidney after placing rodents on a high salt diet. We propose to clone and sequence the control and salt-regulated renal epoxygenase genes and then study the molecular basis for the increase in the level of epoxygenase activity in animals given a high salt diet. In addition, other preliminary evidence outlined in project 2 demonstrates that in the Dahl+ salt sensitive strain of rats there is a lack of induction of epoxygenase activity following salt loading. We also propose to clone the homologue of the salt regulated epoxygenase (SREP) gene from the Dahl+ rat kidney and determine the molecular basis for the absence of salt regulation of this enzyme in the Dahl+ (salt sensitive) rats.
|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