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1 Physiologisches Institut, Universitaet Wuerzburg, Wuerzburg, Germany
2 Department of Physiology, University of Arizona, Tucson, Arizona, USA
* To whom correspondence should be addressed. E-mail: christoph.sauvant{at}mail.uni-wuerzburg.de.
We recently showed that in a proximal tubule cell line (OK cells) EGF stimulates basolateral organic anion transport via ERK1/2, arachidonic acid, phospholipase A2 and generation of prostaglandins. PGE2 binds the prostanoid receptor and thus activates adenylate cyclase and protein kinase A which stimulates basolateral organic anion uptake. In the present study we investigated whether this regulatory cascade is also true for (a) ex-vivo conditions in isolated renal proximal tubules (S2) from rabbit and (b) in a human renal epithelial cell line stably expressing human OAT1 (IHKE-hOAT1). EGF activated ERK1/2 in both S2 tubules and IHKEhOAT1, and in both cases inhibition of ERK activation (by U0126) abolished this stimulation. In both S2 tubules and IHKE-hOAT1, EGF led to an increase of organic anion uptake, which again was inhibited by U0126. PGE2 stimulated basolateral organic anion uptake in rabbit S2 tubules and IHKE-hOAT1. Both EGF- and PGE2-mediated stimulation of organic anion uptake was abolished by inhibition of PKA in rabbit S2 tubules and IHKE-hOAT1, respectively. We conclude, that (a) stimulation of basolateral organic anion uptake by EGF or PGE2 is a widespread (if not general) regulatory mechanism; (b) the signal transduction pathway involved seems to be general, too; (c) stimulation of basolateral organic anion uptake by EGF or PGE2 is also present under ex-vivo conditions and thus is not a cell culture artifact; (d) activation of OAT1 is sufficient to explain the stimulatory effects of EGF and PGE2 in both OK cells and rabbit S2 segments; and (e) stimulation of basolateral OAT1 by EGF or PGE2 is also important in humans and thus may have clinical implications.
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