Molecular Cloning and Characterization of NKT, a Gene Product Related to the Organic Cation Transporter Family That Is Almost Exclusively Expressed in the Kidney

Abstract

We have identified a gene product (NKT) encoding an apparently novel transcript that appears to be related to the organic ion transporter family and is expressed almost exclusively in the kidney. Analysis of the deduced 546-amino acid protein sequence indicates that NKT is a unique gene product which shares a similar transmembrane domain hydropathy profile as well as transporterspecific amino acid motifs with a variety of bacterial and mammalian nutrient transporters. Nevertheless, the overall homology of NKT to two recently cloned organic ion transport proteins (NLT and OCT-1) is significantly greater; together these three gene products may represent a new subgroup of transporters. The NKT was characterized further with respect to its tissue distribution and its expression during kidney development. A 2.5-kilobase transcript was found in kidney and at much lower levels in brain, but not in a number of other tissues. Studies on the embryonic kidney indicate that the NKT transcript is developmentally regulated with significant expression beginning at mouse gestational day 18 and rising just before birth, consistent with a role in differentiated kidney function. Moreover, in situ hybridization detected specific signals in mouse renal proximal tubules. NKT was mapped by linkage disequilibrium to mouse chromosome 19, the same site to which several mouse mutations localize, including that for osteochondrodystrophy (ocd). Although initial experiments in a Xenopus oocyte expression system failed to demonstrate transport of known substrates for OCT-1, the homology to OCT-1 and other transporters, along with the proximal tubule localization, raise the possibility that this gene may play a role in organic solute transport or drug elimination by the kidney.

Cloning and functional expression of a mouse liver organic cation transporter

“…14,[28][29][30][31] Similarly, homologous cDNAs that encode for a polyspecific renal anion transporter, OAT1 (also known as the paraaminohippurate transporter), have been recently identified, but also appear to be kidney-specific. [32][33][34] The rat and human OCT1 are kinetically similar to a renal proximal tubule and hepatocellular basolateral plasma membrane TEA transporter, and functionally characterized by NMN-inhibition of organic cation uptake. In fact, the NMN-inhibitable component of TEA uptake by Xenopus oocytes was the functional characteristic used to clone rOCT1.…”

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

“…This later proved to be true, but only in part, as several other transporters are now known to be involved. Soon after rOat1 had been cloned, other Oat1 orthologs were identified; in human, pig, rabbit, mouse, flounder and C. elegans [43][44][45][46][47][48][49][50][51]. To date, Oat1 message has been detected in kidney, choroid plexus and olfactory mucosa [52][53][54].…”

Analyses of 5′ regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3)

“…Two members of this subfamily, SLC22A6 (also known as OAT1), originally identified as novel kidney transporter (NKT; Lopez-Nieto et al 1996, 1997 and SLC22A8 (also known as OAT3), originally identified as reduced in osterosclerosis (ROCT) (Brady et al 1999), function as the major basolateral transporters of a wide variety of drugs and toxins excreted via the proximal tubule of the kidney. These drugs include nonsteroidal anti-inflammatory drugs, antibiotics, antivirals (such as adefovir and cidofovir), antihypertensives, diuretics, methotrexate and many other commonly prescribed drugs (Eraly et al 2004a, b).…”