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Originally published In Press as doi:10.1074/jbc.M007046200 on February 2, 2001

J. Biol. Chem., Vol. 276, Issue 18, 14695-14703, May 4, 2001
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Modulation of the Basolateral and Apical Step of Transepithelial Organic Anion Secretion in Proximal Tubular Opossum Kidney Cells
ACUTE EFFECTS OF EPIDERMAL GROWTH FACTOR AND MITOGEN-ACTIVATED PROTEIN KINASE*

Christoph SauvantDagger , Hildegard Holzinger, and Michael Gekle

From the Physiologisches Institut der Universität Würzburg, 97070 Würzburg, Germany

The organic anion transport system in the proximal tubule of the kidney is of major importance for the excretion of a variety of endogenous and potentially toxic exogenous substances. Furthermore, the clearance of model substrates (e.g. para-aminohippurate) of this system is used for the determination of renal blood flow. We investigated regulation of organic anion secretion in a way that allowed us to examine simultaneously regulation of overall transepithelial secretion and to estimate the separate contributions of regulation of the basolateral and apical transport steps to this overall regulation. The data were verified by measurement of initial basolateral uptake rate and initial apical efflux rate. Opossum kidney cells were used as a suitable model system for proximal tubule cells, and [14C]para-aminohippurate was utilized as an organic anion. Stimulation of protein kinase C inhibited transepithelial secretion because of inhibition of both apical efflux and basolateral uptake. Inhibition of the mitogen-activated protein kinase (MAPK) kinase MEK reduced transepithelial secretion via inhibition of basolateral uptake and apical efflux. Epidermal growth factor (EGF) enhanced transepithelial secretion via stimulation of basolateral uptake but did not affect apical efflux. EGF induced stimulation of basolateral uptake was abolished by inhibition of MEK. EGF led to phosphorylation of ERK1/2, which was also abolished by inhibition of MEK. Thus, EGF stimulated basolateral uptake of organic anions via MAPKs. Transepithelial organic anion secretion can be regulated at two sites, at least: basolateral uptake and apical efflux. Both steps are under control of protein kinase C and MAPK. The pathophysiologically relevant growth factor EGF enhances transepithelial secretion via stimulation of basolateral uptake. EGF stimulates basolateral uptake via MEK and ERK1/2. Thus, renal organic anion extraction may be modulated, especially under pathophysiological conditions.

* This work was supported by Deutsche Forschungsgemeinschaft Grant Ge 905/3-4.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Physiologisches Inst., Universität Würzburg, Röntenring 9, 97070 Würzburg, Germany. Tel.: 49-931-31-2724; Fax: 49-931-31-2741; E-mail: christoph.sauvant@mail.uni-wuerzburg.de.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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