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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
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
Sauvant ,
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.
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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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.
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