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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|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|
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|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|
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|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|
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