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Epoxyeicosatrienoic acids affect electrolyte transport in renal tubular epithelial cells: dependence on cyclooxygenase and cell polarity

¹Institute of Clinical Pharmacology, Johann Wolfgang Goethe University, Frankfurt; ²Department of Pediatrics, Philipps University, Marburg; ³Vascular Signalling Group, Institute of Cardiovascular Physiology, Johann Wolfgang Goethe-University, Frankfurt, Germany; and ⁴Division of Intramural Research, National Institutes of Health/National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina

Submitted 17 May 2006 ; accepted in final form 2 May 2007

We investigated the effects of epoxyeicosatrienoic acids (EETs) on ion transport in the polarized renal distal tubular cell line, Madin-Darby canine kidney (MDCK) C7. Of the four EET regioisomers (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) studied, only apical, but not basolateral, application of 5,6-EET increased short-circuit current (I_sc) with kinetics similar to those of arachidonic acid. The ion transport was blocked by preincubation with the cyclooxygenase inhibitor indomethacin or with the chloride channel blocker NPPB. Furthermore, both a Cl^–-free bath solution and the Ca²⁺ antagonist verapamil blocked 5,6-EET-induced ion transport. Although the presence of the PGE₂ receptors EP2, EP3, and EP4 was demonstrated, apically added PGE₂ was ineffective and basolaterally added PGE₂ caused a different kinetics in ion transport compared with 5,6-EET. Moreover, PGE₂ sythesis in MDCK C7 cells was unaffected by 5,6-EET treatment. GC/MS/MS analysis of cell supernatants revealed the presence of the biologically inactive 5,6-dihydroxy-PGE₁ in 5,6-EET-treated cells, but not in control cells. Indomethacin suppressed the formation of 5,6-dihydroxy-PGE₁. 5,6-Epoxy-PGE₁, the precursor of 5,6-dihydroxy-PGE₁, caused a similar ion transport as 5,6-EET. Cytochrome P-450 enzymes homolog to human CYP2C8, CYP2C9, and CYP2J2 protein were detected immunologically in the MDCK C7 cells. Our findings suggest that 5,6-EET affects Cl^– transport in renal distal tubular cells independent of PGE₂ but by a mechanism, dependent on its conversion to 5,6-epoxy-PGE₁ by cyclooxygenase. We suggest a role for this P450 epoxygenase product in the regulation of electrolyte transport, especially as a saluretic compound acting from the luminal side of tubular cells in the mammalian kidney.

kidney; CYP450; prostaglandin; collecting duct

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