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Vol. 290, Issue 2, 710-715, August 1999
Department of Pharmacology and Toxicology, Rheinisch
Westfälische Technische Hochschule Aachen, Aachen, Germany
In renal proximal tubules, the basolateral organic anion
[p-aminohippurate (PAH)] transporter is functionally
coupled to the sodium-dependent dicarboxylate transporter. This study
was undertaken to elucidate whether protein kinases differentially
modulate the activities of these transporters. In isolated
S2 segments of proximal tubules microdissected from rabbit
kidneys, we investigated whether the transporters are regulated by
tyrosine kinases, phosphatidylinositol 3-kinase (PI3K), and
mitogen-activated protein kinase (MAPK). The tubules were collapsed;
hence, tubular uptake of the marker substances [3H]PAH
and [14C]glutarate reflects transport across the
basolateral cell membrane. Genistein, a selective inhibitor of tyrosine
kinase, diminished PAH uptake at 10
7 M by 15.6 ± 11.7% and at 106 M by 25.6 ± 9.1%. An inactive
analog of genistein, diadzein, was without effect even at a
concentration 100-fold higher than the lowest concentration of
genistein, which produced significant reduction of PAH uptake. At
107 M, wortmannin, a selective inhibitor of PI3K, reduced
PAH uptake by 24.1 ± 11.3% and, at 106 M, it
reduced it by 32.9 ± 11.8%. The selective inhibitor of MAPK,
PD98059, diminished PAH uptake at 5 × 105 M by
23.2 ± 6.8% and at 104 M by 18.3 ± 5.2%.
Glutarate uptake was not reduced by any of these protein kinase
inhibitors. Insulin had no effect on PAH uptake. These findings
indicate that, in addition to protein kinase A, protein kinase C and
calcium/calmodulin-dependent protein kinase II (former studies from
this laboratory), as well as tyrosine kinases, PI3K, and MAPK, modulate
renal basolateral PAH transport, whereas none of these protein kinases
affects basolateral glutarate transport. Thus, the results provide
evidence for differential regulation of basolateral transporters for
PAH and dicarboxylates.
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