Epoxyeicosatrienoic Acids Regulate Na Transport in CCD

$460,233P01FY2007HLNIH

New York Medical College, Valhalla NY

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Abstract

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

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