The molecular and cellular physiology of basolateral organic anion transport in mammalian renal tubules

被引:66
作者
Dantzler, WH [1 ]
Wright, SH [1 ]
机构
[1] Univ Arizona, Hlth Sci Ctr, Dept Physiol, Coll Med, Tucson, AZ 85724 USA
来源
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES | 2003年 / 1618卷 / 02期
关键词
renal tubule; organic anion; basolateral transport; OAT1; OAT3;
D O I
10.1016/j.bbamem.2003.08.015
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Basolateral transport of organic anions (OAs) into mammalian renal proximal tubule cells is a tertiary active transport process. The final step in this process involves movement of OA into the cells against its electrochemical gradient in exchange for alpha-ketoglutarate (alphaKG) moving down its electrochemical gradient. Two homologous transport proteins (OAT1 and OAT3) that function as basolateral OA/alphaKG exchangers have been cloned and sequenced. We are in the process of determining the functional distribution and regulation of OAT1 and OAT3 in renal tubules. We are using rabbit OATI (rbOAT1) and OAT3 (rbOAT3) expressed in heterologous cell systems to determine substrate specificity and putative regulatory steps and isolated rabbit proximal renal tubule segments to determine functional distribution and physiological regulation of these transporters within their native epithelium. Rabbit OATI and OAT3 differ distinctly in substrate specificity. For example, rbOAT1 has a high affinity for the classical renal OA transport substrate, p-aminohippurate (PAH), whereas rbOAT3 has no affinity for PAH. In contrast, rbOAT3 has a high affinity for estrone sulfate (ES), whereas rbOAT1 has only a very slight affinity for ES. Both rbOAT1 and rbOAT3 appear to have about the same affinity for fluorescein (FL). These differences and similarities in substrate affinities make it possible to functionally map transporters along the renal tubules. Initial data indicate that OATI predominates in S2 segments of the rabbit proximal tubules, but studies of other segments are just beginning. Transport of a given substrate in any tubule segment depends on both the affinity of each transporter which can accept that substrate as well as the level of expression of each of those processes in that particular tubule segment. Basolateral PAH transport (presumably OATI activity) appears to be down-regulated by activation of protein kinase C (PKC) and up-regulated via mitogen-activated protein kinase (MAPK) through phospholipase A(2)(PLA(2)) prostaglandin E-2 (PGE(2)), cyclic AMP, and protein kinase A (PKA) activation. (C) 2003 Elsevier B.V. All rights reserved.
引用
收藏
页码:185 / 193
页数:9
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