Short-term regulation of basolateral organic anion uptake in proximal tubular OK cells:: EGF acts via MAPK, PLA2, and COX1

被引:28
作者
Sauvant, C [1 ]
Holzinger, H [1 ]
Gekle, M [1 ]
机构
[1] Univ Wurzburg, Inst Physiol, D-97070 Wurzburg, Germany
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2002年 / 13卷 / 08期
关键词
D O I
10.1097/01.ASN.0000024437.62046.AF
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
The organic anion transport system of the kidney is of major importance for the excretion of a variety of endogenous compounds, drugs, and potentially toxic substances. The basolateral uptake into proximal tubular cells is mediated by a tertiary active transport system. Epidermal growth factor (EGF) leads to an increase in the basolateral uptake rate of the model substrate para-aminohippuric acid (PAH) in opossum kidney (OK) cells. This stimulation is mediated by successive activation of the mitogen-activated protein kinases, mitogen-activated/extracellular signal-regulated kinase kinase (MEK) and extracellular regulated kinase isoforms 1 and 2 (ERK1/2). This study investigates the regulatory network of EGF action on PAH uptake downstream ERK1/2 in more detail. EGF stimulation of the basolateral uptake rate of [C-14]PAH was abolished by the phospholipase A(2) inhibitor AACOCF3. [C-14]PAH uptake was enhanced by arachidonic acid. Furthermore, EGF led to an increase in arachidonic acid release and to the generation of prostaglandins. AACOCF3 did not influence EGF-induced ERK1/2 activation, indicating that ERK1/2 is upstream of PLA(2). In addition, EGF stimulated the influx of extracellular Ca2+. However, Ca2+-influx was not required for the stimulatory action of EGF on [C-14]PAH uptake. Inhibitors of COX and lipoxygenases reduced [C-14]PAH uptake dose-dependently, whereas inhibition of cytochrome P450 did not. In the presence of indomethacin, EGF had no stimulatory effect on [C-14]PAH uptake. The inhibitory effect of indomethacin was not due to competitive action on PAH uptake. Furthermore, prostaglandin E-2 (PGE(2)) increased basolateral [C-14]PAH uptake rate dose-dependently, and this increase was also observed in the presence of indomethacin. Selective inhibition of COX2 by indomethacin amid or indomethacin n-heptyl ester did not inhibit [C-14]PAH uptake, whereas selective inhibition of COX1 dose-dependently inhibited [C-14]PAH uptake. This and previous data lead to the conclusion that EGF successively activates MEK, ERK1/2, and PLA(2), leading to an increased release of arachidonic acid. Subsequently, arachidonic acid is metabolized to prostaglandins via COX1, which then mediate EGF-induced stimulation of basolateral organic anion uptake rate.
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页码:1981 / 1991
页数:11
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