Naslov
Murine renal Organic Anion Transporters mOAT1 and mOAT3 facilitate the transport of neuroactive tryptophan metabolites

Autori
Bahn, Andrew ; Ljubojević, Marija ; Lorenz, Heiko ; Schultz, Christian ; Ghebremedhin, Estifanos ; Ugele, Bernhard ; Sabolić, Ivan ; Burckhardt, Gerhard ; Hagos, Yohannes

Izvornik
American journal of physiology. Cell physiology (0363-6143) 289 (2005); C1075-C1084

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
kidneys; brain; macula densa; transforming growth factor; N-methyl-D-aspartate receptor

Sažetak
Tryptophan metabolites such as kynurenate (KYNA), xanthurenate (XA), and quinolinate are considered to have an important impact on many physiological processes, especially on brain function. Many of these metabolites are secreted with the urine. Since Organic-Anion-Transporters (OATs) facilitate the renal secretion of weak organic acids, we investigated whether the secretion of bioactive tryptophan metabolites is mediated by OAT1 and OAT3, two prominent members of the OAT-family. Immunohistochemical analyses of the mouse kidneys revealed the expression of OAT1 to be restricted to the proximal convoluted tubule (representing S1 and S2 segments), whereas OAT3 was detected in almost all parts of the nephron including macula densa cells. In the mouse brain, OAT1 was found to be expressed in neurons of the cortex cerebri and hippocampus, as well as in the ependymal cell layer of the choroid plexus. Six tryptophan metabolites, among them the bioactive substances kynurenate, xanthurenate, and the serotonin metabolite 5-hydroxyindol-acetate inhibited [3H]PAH or 6-CF uptake by 50-85%, demonstrating that these compounds interact with OAT1 as well as OAT3. Half-maximal inhibition of mOAT1 occurred at 34 µ M (KYNA) and 15 µ M (XA), and at 8 µ M (KYNA) and 11.5 µ M (XA) for mOAT3. Quinolinate showed a slight, but significant inhibition of [3H]PAH uptake by mOAT1 and no alteration of 6-CF uptake by mOAT3. [14C]glutarate (GA) uptake was examined for both transporters illustrating differences in the transport rate for this substrate by a factor of 4. Transstimulation experiments with [14C]glutarate revealed that KYNA and XA are substrates for mOAT1. Our results support the idea that OAT1 and OAT3 are involved in the secretion of bioactive tryptophan metabolites from the body. Consequently, they are crucial for the regulation of central nervous tryptophan metabolite concentration.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA