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.

Public Health Relevance

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 .

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York Medical College
United States
Zip Code
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
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
Bowden, John A; Heckert, Alan; Ulmer, Candice Z et al. (2017) Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma. J Lipid Res 58:2275-2288
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
Sodhi, Komal; Srikanthan, Krithika; Goguet-Rubio, Perrine et al. (2017) pNaKtide Attenuates Steatohepatitis and Atherosclerosis by Blocking Na/K-ATPase/ROS Amplification in C57Bl6 and ApoE Knockout Mice Fed a Western Diet. Sci Rep 7:193
Chen, Li; Joseph, Gregory; Zhang, Frank F et al. (2016) 20-HETE contributes to ischemia-induced angiogenesis. Vascul Pharmacol 83:57-65
Qin, Jun; Le, Yicong; Froogh, Ghezal et al. (2016) Sexually dimorphic adaptation of cardiac function: roles of epoxyeicosatrienoic acid and peroxisome proliferator-activated receptors. Physiol Rep 4:
Singh, Shailendra P; Schragenheim, Joseph; Cao, Jian et al. (2016) PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: Role of epoxyeicosatrienoic acid. Prostaglandins Other Lipid Mediat 125:8-18
Su, Xiao-Tong; Zhang, Chengbiao; Wang, Lijun et al. (2016) Disruption of KCNJ10 (Kir4.1) stimulates the expression of ENaC in the collecting duct. Am J Physiol Renal Physiol 310:F985-93

Showing the most recent 10 out of 461 publications