The cortical collecting duct (CCD) is responsible for the hormone-regulated Na reabsorption. The Natransport in the CCD is a two-step process:Na enters the cell across the apical membrane through theepithelial 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 Natransport rate is also affected by the cell membrane potential because the Na transport is an electrogenicprocess. Thus, an alteration in cell membrane potential by changing basolateral K channel activity shouldaffect Na transport in the CCD. Our preliminary data have demonstrated that arachidonic acid (AA) inhibitsthe activity of ENaC and the basolateral K channels and that the effect of AA on ENaC and basolateral Kchannels is abolished by blocking CYP epoxygenase-dependent metabolism of AA. Also, 11,12epoxyeicosatrienoic acid (EET), a product of CYP-epoxygenase-dependet AA metabolite, mimic theeffect of AA on ENaC. Thus, we will test the hypothesis that EET suppresses Na transport by inhibitingENaC and basolateral K channels in the CCD and that the inhibitory effect of EET is enhanced by a highNa intake.
Specific Aim 1 : To test that Na intake modulates the inhibitory effect of AA on ENaC by changing CYPEpoxygenase 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 inhibitbasolateral K channels in the CCD.
Specific Aim 3 : To test the hypothesis that stimulation of adenosine receptor inhibits ENaC and thebasolateral 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 isinvolved in mediatina the effect of EET on ENaC.
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