Epoxyeicosatrienoic Acids Regulate Na Transport in CCD

皮质收集管（CCD）负责激素调节的钠重吸收。Na

The cortical collecting duct (CCD) is responsible for the hormone-regulated Na reabsorption. The Na transport in the CCD is a two-step process:Na enters the cell across the apical membrane through the epithelial Na channel (ENaC) and Na is extruded across the basolateral membrane via Na-K-ATPase. Apical Na conductance is a rate limiting step for the Na reabsorption in the CCD. In addition, the Na transport rate is also affected by the cell membrane potential because the Na transport is an electrogenic process. Thus, an alteration in cell membrane potential by changing basolateral K channel activity should affect Na transport in the CCD. Our preliminary data have demonstrated that arachidonic acid (AA) inhibits the activity of ENaC and the basolateral K channels and that the effect of AA on ENaC and basolateral K channels is abolished by blocking CYP epoxygenase-dependent metabolism of AA. Also, 11,12 epoxyeicosatrienoic acid (EET), a product of CYP-epoxygenase-dependet AA metabolite, mimic the effect of AA on ENaC. Thus, we will test the hypothesis that EET suppresses Na transport by inhibiting ENaC and basolateral K channels in the CCD and that the inhibitory effect of EET is enhanced by a high Na intake. Specific Aim 1: To test that Na intake modulates the inhibitory effect of AA on ENaC by changing CYP Epoxygenase activity and that EET also is involved in mediating the feedback-regulation of ENaC. Specific Aim 2: To test the hypothesis that CYP-epoxygenase dependent metabolites of AA inhibit basolateral K channels in the CCD. Specific Aim 3: To test the hypothesis that stimulation of adenosine receptor inhibits ENaC and the basolateral K channels in the CCD via CYP-epoxygenase dependent AA metabolites. Specific Aim 4: To test the hypothesis that the interaction of EET with other cell signaling pathways is involved in mediatina the effect of EET on ENaC.