Molecular physiology of renal organic anion transporters

Abstract

Recent advances in molecular biology have identified three organic anion transporter families: the organic anion transporter (OAT) family encoded by SLC22A, the organic anion transporting peptide (OATP) family encoded by SLC21A (SLCO), and the multidrug resistance-associated protein (MRP) family encoded by ABCC. These families play critical roles in the transepithelial transport of organic anions in the kidneys as well as in other tissues such as the liver and brain. Among these families, the OAT family plays the central role in renal organic anion transport. Knowledge of these three families at the molecular level, such as substrate selectivity, tissue distribution, and gene localization, is rapidly increasing. In this review, we will give an overview of molecular information on renal organic anion transporters and describe recent topics such as the regulatory mechanisms and molecular physiology of urate transport. We will also discuss the physiological roles of each organic anion transporter in the light of the transepithelial transport of organic anions in the kidneys.OAT; urate; organic anion transporting peptide; multidrug resistance-associated protein THE ORGANIC ANION (OA) transport system has been a major subject in renal physiology over the past 100 years, because this system represents the tubular secretory pathway. OAs include numerous substances of both endogenous and exogenous origins, and the renal OA transport system plays a pivotal role in the elimination of potentially toxic compounds including metabolites, xenobiotics, and drugs. Because of its complexity, there are still limitations in a detailed analysis of the renal OA transport system by physiological techniques. A notable advance was made in the 1990s by the identification of three major organic anion transporter families: the OAT (organic anion transporter) family encoded by SLC22A, the organic anion transporting peptide (OATP) family encoded by SLCO, and the multidrug resistance-associated protein (MRP) family encoded by ABCC (ATP-binding cassette) superfamily. The identification of each transporter enabled us to perform precise functional analyses of the system. Molecular knowledge in this area has rapidly increased, and various information has appeared within the last few years. In this review, first, we will give an overview of molecular information on OA transporters. Then, we will focus on recent advances, particularly those in the study of the OAT family, which represents the major and classic renal OA transport system. With regard to the OATP and MRP families, we will touch only potentially important points in renal physiology. The major topics described in this paper are as follows: 1) regulatory mechanisms of OA transporters, such as gender differences, intracellular signaling, genomic organization, pathophysiological states and scaffolding proteines; 2) molecular physiology of the renal urate transporter; and 3) organization of transepithelial transport of organic anions. For historical and physiological backgrounds on renal OA...

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