Developmentally regulated expression of organic ion transporters NKT (OAT1), OCT1, NLT (OAT2), and Roct

Abstract

Several xenobiotic (organic cation and anion) transporters have recently been identified, although their endogenous substrates, if such exist, remain unknown. When we initially identified NKT, also known as OAT1, the first member of the organic anion transporter (OAT) family (Lopez-Nieto CE, You G, Bush KT, Barros EJ, Beier DR, and Nigam SK. J Biol Chem 272: 6471-6478, 1997), we noted its expression in the embryonic kidney. We have now demonstrated its transporter function and more fully examined the spatiotemporal expression patterns of representative organic ion transporters, [NKT (OAT1), Roct, OCT1, and NLT, also known as OAT2] during murine development. In the kidney, NKT (OAT1), OCT1, and Roct transcripts appeared at midgestation, coinciding with proximal tubule differentiation, and gradually increased during nephron maturation. A similar pattern was observed for NLT (OAT2) in the liver and kidney, although, in the kidney, NLT (OAT2) transcription did not increase as dramatically. The roughly cotemporal expression of these related transporters in the developing proximal tubule may indicate common transcriptional regulation. Expression during embryogenesis in extrarenal sites could suggest a role in the formation and maintenance of nonrenal tissues. Importantly, all four genes were expressed in unexpected places during nonrenal organogenesis: Roct in the fetal liver (temporally coinciding with the onset of hematopoiesis) and neural tissue; NKT (OAT1) in the fetal brain; OCT1 in the ascending aorta and atrium; and NLT (OAT2) in the fetal lung, intestine, skin, and developing bone. Because these gene products mediate the transport of a broad range of metabolites and toxins, it seems likely that, apart from their known functions, these transporters play a role in transport of organic molecules, perhaps including those with morphogenetic activity. These genes could also play important developmental roles independent of transport function.

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

“…Human pediatric kidney data remain limited, so what we currently know, especially from a mechanistic standpoint, comes largely from a limited number of rodent studies. For example, it is known that drug transporter expression occurs early in embryogenesis; indeed, several renal drug transporters are expressed transiently in the developing central nervous system and other tissues (94). Late in rodent gestation, the expression is largely limited to the future proximal tubules of the kidney (15,95); thereafter, there is a burst in renal expression around the time of birth, eventually reaching (and perhaps overshooting for a short time) adult expression (9,96).…”

RAT AND MOUSE DIFFERENCES IN GENDER-PREDOMINANT EXPRESSION OF ORGANIC ANION TRANSPORTER (OAT1–3;SLC22A6–8) mRNA LEVELS

“…Oat1 mRNA was initially detected in kidney and brain on embryonic day 14. Kidney levels rose throughout development, whereas transcript levels in brain decreased between fetal and adult ages (Pavlova et al, 2000).…”

“…Greatest expression was found on embryonic day 19 (LopezNieto et al, 1997). Pavlova et al (2000) also determined prenatal developmental expression of mouse Oat1 mRNA during embryonic days 12 through 18. Oat1 mRNA was initially detected in kidney and brain on embryonic day 14.…”

“…Oat2 (Slc22a7) expression was determined by in situ hybridization in adult mouse kidney and liver, where mRNA levels appeared to be highest in liver (Pavlova et al, 2000). In kidney, expression was localized to the cortex.…”

“…In kidney, expression was localized to the cortex. Additionally, Oat2 expression was determined in mouse kidney, liver, lung, and cartilage at embryonic day 14 (Pavlova et al, 2000). Although Oat2 mRNA levels increased in kidney throughout development, liver levels were consistently higher than those in kidney (Pavlova et al, 2000).…”