Project #4 will invesfigate the role of P450 Arachidonic Acid (AA) metabolites in regulation of both function and growth of renal epithelial cells. Studies performed by this PPG and by others indicate a role for the P450 AA monooxygenase pathway in the pathophysiology of human hypertension, in salt sensitive natriuresis and in the progression of renal disease. There is increasing evidence that both EETs and 20-HETE serve as important natriuretic factors, with direct inhibitory effects on sodium transporters in renal epithelial cells. Based on previous studies by our group and by others, we propose that EETs and 20-HETE serve primarily as intracellular second messengers for certain growth factors and hormones, regulating other signal transduction pathways and ion channels and transporters in renal epithelial cells. Specifically, we will explore their role as second messengers for Epidermal Growth Factor (EGF) and dopamine, two agonists postulated to have important roles in regulafion of renal epithelial salt and water homeostasis. In addifion to their role as second messengers to mediate functional tubule responses, we and others have documented mitogenic and anti-apoptotic effects of P450 AA metabolites in vitro, and we hypothesize that they are also important in protecfion and recovery from ischemic injury of the mammalian kidney in vivo. In order to investigate these issues, we propose the follow specific aims:
Specific Aim I) Investigate intracellular signaling mechanisms of EETs as second messengers for renal EGF receptor activation and functional responses.
Specific Aim II) Investigate the role of P450 AA metabolites as second messengers for dopamine-mediated natriuresis Specific Aim 111) Investigate the role of EETs in cytoprotection and recovery from acute tubule injury We hypothesize that sublethal renal injury may lead to increased P450 expression and function in mammalian kidney to """"""""precondition"""""""" against further ischemia/reperfusion induced injury.
These studies will investigate potential underiying mechanisms regulating salt and water homeostasis by the kidney and will determine if the P450 arachidonic acid metabolites are mediators of net natriuresis. Given the importance of altered kidney regulafion of salt and water in the development/maintenance of hypertension, these studies may provide new insights into pathophysiology. In addifion, these studies will determine if alterations of these compounds mav underiie Dathophvsioloaic alterafions in acute kidnev iniurv.
|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|
|Sporková, Alexandra; Reddy, Rami N; Falck, John R et al. (2016) Interlobular Arteries From 2-Kidney, 1-Clip Goldblatt Hypertensive Rats' Exhibit-Impaired Vasodilator Response to Epoxyeicosatrienoic Acids. Am J Med Sci 351:513-9|
|Miller, Bradley; Palygin, Oleg; Rufanova, Victoriya A et al. (2016) p66Shc regulates renal vascular tone in hypertension-induced nephropathy. J Clin Invest 126:2533-46|
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