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

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-S)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
United States
Zip Code
Gangadhariah, Mahesha H; Luther, James M; Garcia, Victor et al. (2015) Hypertension is a major contributor to 20-hydroxyeicosatetraenoic acid-mediated kidney injury in diabetic nephropathy. J Am Soc Nephrol 26:597-610
Zeng, Fenghua; Miyazawa, Tomoki; Kloepfer, Lance A et al. (2014) Deletion of ErbB4 accelerates polycystic kidney disease progression in cpk mice. Kidney Int 86:538-47
Luther, James M; Byrne, Loretta M; Yu, Chang et al. (2014) Dietary sodium restriction decreases insulin secretion without affecting insulin sensitivity in humans. J Clin Endocrinol Metab 99:E1895-902
Bajpai, Prachi; Srinivasan, Satish; Ghosh, Jyotirmoy et al. (2014) Targeting of splice variants of human cytochrome P450 2C8 (CYP2C8) to mitochondria and their role in arachidonic acid metabolism and respiratory dysfunction. J Biol Chem 289:29614-30
Hye Khan, Md Abdul; Pavlov, Tengis S; Christain, Sarah V et al. (2014) Epoxyeicosatrienoic acid analogue lowers blood pressure through vasodilation and sodium channel inhibition. Clin Sci (Lond) 127:463-74
Keller, Julia; Ellieva, Alexandra; Ma, Dengke K et al. (2014) CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation. Biochem J 464:61-71
Chen, Li; Ackerman, Rachel; Saleh, Mohamed et al. (2014) 20-HETE regulates the angiogenic functions of human endothelial progenitor cells and contributes to angiogenesis in vivo. J Pharmacol Exp Ther 348:442-51
Wang, Wen-Hui; Zhang, Chengbiao; Lin, Dao-Hong et al. (2014) Cyp2c44 epoxygenase in the collecting duct is essential for the high K+ intake-induced antihypertensive effect. Am J Physiol Renal Physiol 307:F453-60
Nithipatikom, Kasem; Endsley, Michael P; Pfeiffer, Adam W et al. (2014) A novel activity of microsomal epoxide hydrolase: metabolism of the endocannabinoid 2-arachidonoylglycerol. J Lipid Res 55:2093-102
Falck, John R; Koduru, Sreenivasulu Reddy; Mohapatra, Seetaram et al. (2014) 14,15-Epoxyeicosa-5,8,11-trienoic Acid (14,15-EET) surrogates: carboxylate modifications. J Med Chem 57:6965-72

Showing the most recent 10 out of 260 publications