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 .
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