CYP epoxygenase-dependent arachidonic acid (AA) metabolite, 11,12-epoxyeicosatrienoic acid (EET), inhibits epithelial Na channel (ENaC) in the cortical collecting duct (CCD). The main goal ofthe present proposal is to examine the role of a high K (HK) intake and angiotensin II (Angll) in regulating the effect of CYP2C44-dependent AA metabolism on ENaC in the CCD. A HK intake has been shown to increase renal Na excretion thereby antagonizing the high salt intake-induced hypertension. However, the mechanism by which a HK intake minimizes the salt-intake-induced hypertension is not completely understood. Our recent study demonstrates that a HK intake stimulates the expression of CYP2C44 homologue in the rat kidney. Our preliminary data have also shown that AA fails while 11,12-EET is capable to block ENaC in the CCD of CYP2C44(-/-) mice, suggesting that CYP2C44-dependent 11,12-EET generation is responsible for AAmediated inhibition of ENaC. Genetic deletion of CYP2C44 also causes the salt-sensitive and dietary Ksensitive hypertension. Thus, we will test the hypothesis that 11,12-EETgenerated by CYP2C44 homologue in the aldosterone-sensitive nephron (ASDN) is a HK-induced antihypertensive factor which inhibit ENaC and Na absorption in ASDN. The effect of a HK intake on CYP2C44 activity may be the result of suppressing type I angiotensin 11 receptor (AT1R) because Inhibiting ATI R with valsartan or deleting ATI R mimics the effect of a HK intake and stimulates CYP2C44 expression and enhances AA-induced inhibition of ENaC in tem (RAS) enhances whereas stimulation of RAS diminishes the inhibitory effect of CYP2C44-dependent AA metabolism on ENaC and Na transport in the ASDN. We propose to test that CYP2C44-dependent AA metabolism inhibits Na transport and ENaC in ASDN in response to a HK intake;to investigate whether suppressing AT1R by a HK intake is responsible for enhancing AA and 11,12-EET-mediated inhibition of ENaC;and to test that Angll stimulates ENaC through suppressing CYP-epoxygenase and increasing reactive oxygen species (ROS) generation which minimizes the inhibitory effect of AA and 11,12-EET on ENaC.
The physiological relevance of the study is to illustrate the underiying mechanism by which a HK intake suppresses renal Na transport in the ASDN and decreases blood pressure. In addition, the proposal will identify a novel mechanism by which Angll stimulates Na transport in the ASDN by suppressing CYPepoxygenase dependent metabolism and minimizing EET-induced inhibition of ENaC .
|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|
|Rocic, Petra; Schwartzman, Michal Laniado (2018) 20-HETE in the regulation of vascular and cardiac function. Pharmacol Ther 192:74-87|
|Singh, S P; McClung, J A; Bellner, L et al. (2018) CYP-450 Epoxygenase Derived Epoxyeicosatrienoic Acid Contribute To Reversal of Heart Failure in Obesity-Induced Diabetic Cardiomyopathy via PGC-1 ? Activation. Cardiovasc Pharm Open Access 7:|
|Schragenheim, Joseph; Bellner, Lars; Cao, Jian et al. (2018) EET enhances renal function in obese mice resulting in restoration of HO-1-Mfn1/2 signaling, and decrease in hypertension through inhibition of sodium chloride co-transporter. Prostaglandins Other Lipid Mediat 137:30-39|
|Soler, Amanda; Hunter, Ian; Joseph, Gregory et al. (2018) Elevated 20-HETE in metabolic syndrome regulates arterial stiffness and systolic hypertension via MMP12 activation. J Mol Cell Cardiol 117:88-99|
|Wang, Lijun; Zhang, Chengbiao; Su, Xiao-Tong et al. (2017) PGF2?regulates the basolateral K channels in the distal convoluted tubule. Am J Physiol Renal Physiol 313:F254-F261|
|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|
|Pandey, Varunkumar; Garcia, Victor; Gilani, Ankit et al. (2017) The Blood Pressure-Lowering Effect of 20-HETE Blockade in Cyp4a14(-/-) Mice Is Associated with Natriuresis. J Pharmacol Exp Ther 363:412-418|
|Zhang, Bin; Kandhi, Sharath; Yang, Yang-Ming et al. (2017) A novel mechanism of ascorbate direct modulation of soluble epoxide hydrolase. Prostaglandins Other Lipid Mediat 131:59-66|
|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|
Showing the most recent 10 out of 468 publications