Project #4 will investigate 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 regulation of renal epithelial salt and water homeostasis. In addition 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 protection 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 III) 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
These studies will investigate potential underlying 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 regulation of salt and water in the development/maintenance of hypertension, these studies may provide new insights into pathophysiology. In addition, these studies will determine if alterations of these compounds may underlie Dathophvsioloaic alterations in acute kidney injury.
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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|
|SporkovÃ¡, 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|
|Paudyal, Mahesh P; Adebesin, Adeniyi Michael; Burt, Scott R et al. (2016) Dirhodium-catalyzed C-H arene amination using hydroxylamines. Science 353:1144-7|
|Luther, James M; Brown, Nancy J (2016) Epoxyeicosatrienoic acids and glucose homeostasis in mice and men. Prostaglandins Other Lipid Mediat 125:2-7|
|Chen, Li; Joseph, Gregory; Zhang, Frank F et al. (2016) 20-HETE contributes to ischemia-induced angiogenesis. Vascul Pharmacol 83:57-65|
|Garcia, Victor; Joseph, Gregory; Shkolnik, Brian et al. (2015) Angiotensin II receptor blockade or deletion of vascular endothelial ACE does not prevent vascular dysfunction and remodeling in 20-HETE-dependent hypertension. Am J Physiol Regul Integr Comp Physiol 309:R71-8|
|Capdevila, Jorge H; Wang, Wenhui; Falck, John R (2015) Arachidonic acid monooxygenase: Genetic and biochemical approaches to physiological/pathophysiological relevance. Prostaglandins Other Lipid Mediat 120:40-9|
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