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Role of cytochrome P-450 epoxygenase metabolites in EGF signaling in renal proximal tubule.

Burns KD, Capdevila J, Wei S, Breyer MD, Homma T, Harris RC
Am J Physiol. 1995 269 (4 Pt 1): C831-40

PMID: 7485450 · DOI:10.1152/ajpcell.1995.269.4.C831

Epidermal growth factor (EGF) is a potent epithelial cell mitogen and induces eicosanoid production in many cell types. The present study examined signaling mechanisms for EGF in the renal proximal tubule, where high concentrations of cytochrome P-450 epoxygenase have been reported. In primary cultures of rabbit proximal tubule cells, EGF (30 nM) increased endogenous epoxyeicosatrienoic acid (EET) levels 5.3 +/- 1.4-fold within 10 min (n = 6). In these cells EGF-stimulated [3H]thymidine incorporation was significantly inhibited by the cytochrome P-450 inhibitors ketoconazole or clotrimazole but not by the cyclooxygenase inhibitor indomethacin. In fura 2-loaded proximal tubule cells, EGF caused a concentration-dependent increase in cytosolic Ca2+ concentration ([Ca2+]i), due to Ca2+ influx, which was inhibited by either ketoconazole or SKF-525A but not by indomethacin. Addition of 5,6-EET (0.5 microM) also induced Ca2+ influx in proximal tubule cells, whereas 8,9-11,12-, or 14,15-EET did not. In cells treated with bis(2-amino-5-methylphenoxy)ethane N,N,N',N'-tetraacetic acid tetraacetoxy-methyl ester to chelate [Ca2+]i, EGF-stimulated [3H]thymidine incorporation. These results indicate that EGF increases EET levels in proximal tubule and suggest that 5,6-EET or its metabolites may be a modulator of EGF-induced [Ca2+]i increases and involved in mitogenesis.

MeSH Terms (16)

8,11,14-Eicosatrienoic Acid Animals Calcium Cells, Cultured Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System Cytosol Epidermal Growth Factor Female Inositol Phosphates Kidney Tubules, Proximal Mitosis Osmolar Concentration Oxygenases Rabbits Signal Transduction

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