Renal Transporters

ORGANIC CATION TRANSPORT Structurally diverse organic cations are secreted in the proximal tubule. Many secreted organic cations are endogenous compounds (e.g., choline, N-methylnicotinamide, and dopamine), and renal secretion appears to be important in eliminating excess concentrations of these substances. However, a primary function of organic cation secretion is to rid the body of xenobiotics, including many positively charged drugs and their metabolites (e.g., cimetidine, ranitidine, metformin, procainamide, and N-acetylprocainamide), and toxins from the environment (e.g., nicotine). Organic cations that are secreted by the kidney may be either hydrophobic or hydrophilic. Hydrophilic organic drug cations generally have molecular weights of <400; a current model for their secretion in the proximal tubule of the nephron is shown in Figure 2-7.

For the transepithelial flux of a compound (e.g., secretion), it is essential for the compound to traverse two membranes sequentially, the basolateral membrane facing the blood side and the apical membrane facing the tubular lumen. Distinct transporters on each membrane mediate the sequential steps of transport. Organic cations cross the basolateral membrane by three distinct transporters in the SLC family 22 (SLC22): OCT1 (SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). Organic cations are transported across this membrane down their electrochemical gradient (-70 mV). The SLC22 members have 12 putative transmembrane domains with N-linked glycosylation sites.

Transport of organic cations from cell to tubular lumen across the apical membrane occurs via an electroneutral proton-organic cation exchange mechanism. Transporters on the apical

FIGURE 2-7 Model of organic cation secretory transporters in the proximal tubule. Hexagons depict transporters in the SLC22 family, SLC22A1 (OCT1), SLC22A2 (OCT2), and SLC22A3 (OCT3). Circles show transporters in the same family, SLC22A4 (OCTN1) and SLC22A5 (OCTN2). MDR1 (ABCB1) is depicted as a dark blue oval. Carn, carnitine; OC+, organic cation.

FIGURE 2-7 Model of organic cation secretory transporters in the proximal tubule. Hexagons depict transporters in the SLC22 family, SLC22A1 (OCT1), SLC22A2 (OCT2), and SLC22A3 (OCT3). Circles show transporters in the same family, SLC22A4 (OCTN1) and SLC22A5 (OCTN2). MDR1 (ABCB1) is depicted as a dark blue oval. Carn, carnitine; OC+, organic cation.

membrane are in the SLC22 family and termed novel organic cation transporters (OCTNs) OCTN1 (SLC22A4) and OCTN2 (SLC22A5). These bifunctional transporters mediate both organic cation secretion and carnitine reabsorption. In the reuptake mode, the transporters function as Na+ cotransporters, relying on the inwardly driven Na+ gradient created by Na+,K+-ATPase to move carnitine from tubular lumen into the cell. In the secretory mode, the transporters function as proton-organic cation exchangers: protons move from tubular lumen to cell interior in exchange for organic cations, which move from cytosol to tubular lumen.

OCT1 has four splice variants, one of which is functionally active, OCT1G/L554. OCT1 is expressed primarily in the liver, with some expression in heart, intestine, and skeletal muscle. In humans, very modest levels of OCT1 transcripts are detected in the kidney. The transport mechanism of OCT1 is electrogenic and saturable for transport of small-molecular-weight organic cations including tetraethylammonium (TEA) and dopamine. OCT1 also can mediate organic cation-organic cation exchange. Organic cations can trans-inhibit OCT1. When present on the cytosolic side of a membrane, the hydrophobic organic cations quinine and quinidine, which are poor substrates of OCT1, can trans-inhibit influx of organic cations via OCT1.

Human OCT1 (SLC22A1) accepts a wide array of monovalent organic cations with molecular weights of <400, including many drugs (e.g., procainamide, metformin, and pindolol). Inhibitors of OCT1 are generally more hydrophobic. Since OCT1 mammalian orthologs have >80% amino acid identity, evolutionarily nonconserved residues among mammalian species clearly are involved in specificity differences.

OCT2 is located adjacent to OCT1 on chromosome 6 (6q26). A single splice variant of human OCT2, termed OCT2-A, in the kidney is a truncated form of OCT2 that appears to have a lower Km for substrates than OCT2. In the kidney, OCT2 is localized to the proximal tubule, distal tubules, and collecting ducts. In the proximal tubule, OCT2 is restricted to the basolateral membrane. The transport mechanism of OCT2 is similar to that of OCT1.

Like OCT1, OCT2 generally accepts a wide array of monovalent organic cations with molecular weights of <400. OCT2 is also present in neuronal tissues and may play a housekeeping role in neurons, taking up excess concentrations of neurotransmitters and recycling neurotransmitters by taking up breakdown products that then reenter monoamine synthetic pathways.

Human OCT3 is expressed in the liver, kidney (weakly), intestine, and placenta. Like OCT1 and OCT2, OCT3 appears to support electrogenic potential-sensitive organic cation transport. Some studies have suggested that OCT3 is the extraneuronal monoamine transporter based on its substrate specificity and potency of interaction with monoamine neurotransmitters. Because of its relatively low abundance in the kidney, OCT3 may play only a limited role in renal drug elimination.

OCTN1 (SLC22A4) is expressed in the kidney, trachea, and bone marrow and operates as an organic cation-proton exchanger. OCTN1 likely functions as a bidirectional pH- and ATP-dependent transporter at the apical membrane in renal tubular epithelial cells.

OCTN2 (SLC22A5) is expressed predominantly in the renal cortex, with very little expression in the medulla, and is localized to the apical membrane of the proximal tubule. OCTN2 transports L-carnitine with high affinity in a Na+-dependent manner, whereas, Na+ does not influence OCTN2-mediated transport of organic cations. Thus, OCTN2 is thought to function as both a Na+-dependent carnitine transporter and a Na+-independent organic cation transporter. Mutations in OCTN2 cause primary systemic carnitine deficiency.

ORGANIC ANION TRANSPORT Structurally diverse organic anions are secreted in the proximal tubule. The primary function of organic anion secretion appears to be the removal from the body of xenobiotics, including many weakly acidic drugs (e.g., pravastatin, captopril, p-amino-hippurate [PAH], and penicillins) and toxins (e.g., ochratoxin).

Two primary transporters on the basolateral membrane (Figure 2-8) mediate the flux of organic anions from interstitial fluid to tubule cells: OAT1 (SLC22A6) and OAT3 (SLC22A8). Hydrophilic organic anions are transported across the basolateral membrane against an electrochemical gradient in exchange with intracellular a-ketoglutarate, which moves down its concentration gradient from cytosol to blood. The outwardly directed gradient of a-ketoglutarate is maintained by a basolateral Na+-dicarboxylate transporter (NaDC3). The Na+ gradient that drives NaDC3 is maintained by Na+,K+-ATPase.

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