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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK038226-23
Application #
7758890
Study Section
Special Emphasis Panel (ZDK1-GRB-S (M3))
Project Start
2009-09-05
Project End
2014-06-30
Budget Start
2009-09-05
Budget End
2010-06-30
Support Year
23
Fiscal Year
2009
Total Cost
$232,500
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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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
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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
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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

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