Role of blood–brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain

Abstract

Renal impairment is associated with CNS dysfunctions and the accumulation of uremic toxins, such as indoxyl sulfate, in blood. To evaluate the relevance of indoxyl sulfate to CNS dysfunctions, we investigated the brain-to-blood transport of indoxyl sulfate at the blood-brain barrier (BBB) using the Brain Efflux Index method. [ 3 H]Indoxyl sulfate undergoes efflux transport with an efflux transport rate of 1.08 · 10 )2 /min, and the process is saturable with a K m of 298 lM. This process is inhibited by para-aminohippuric acid, probenecid, benzylpenicillin, cimetidine and uremic toxinins, such as hippuric acid and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid. RT-PCR revealed that an OAT3 mRNA is expressed in conditionally immortalized rat brain capillary endothelial cell lines and rat brain capillary fraction. Xenopus oocytes expressing OAT3 were found to exhibit [ 3 H]indoxyl sulfate uptake, which was significantly inhibited by neurotransmitter metabolites, such as homovanillic acid and 3-methoxy-4-hydroxymandelic acid, and by acyclovir, cefazolin, baclofen, 6-mercaptopurine, benzoic acid, and ketoprofen. These results suggest that OAT3 mediates the brain-to-blood transport of indoxyl sulfate, and is also involved in the efflux transport of neurotransmitter metabolites and drugs. Therefore, inhibition of the brainto-blood transport involving OAT3 would occur in uremia and lead to the accumulation of neurotransmitter metabolites and drugs in the brain. Keywords: blood-brain barrier, efflux transport, indoxyl sulfate, organic anion transporter 3 (OAT3), uremic toxin.

Contribution of Organic Anion Transporter 3 (Slc22a8) to the Elimination of p-Aminohippuric Acid and Benzylpenicillin across the Blood-Brain Barrier

“…In the RT-PCR analysis (Fig. 1A), the amplified product of rOat3 was detected in the brain capillary-enriched fraction as well as in the kidney, which corresponds to a previous report (Ohtsuki et al, 2002). In contrast, no expression of rOat1 or rOat2 at the BBB was detected in this study.…”

“…rOat3 accepts amphipathic organic anions such as E 2 17␤G and E 1 S as well as PAH as its substrates (Kusuhara et al, 1999;Sugiyama et al, 2001). In the brain, rOat3 has been shown to be expressed in the choroid plexus (Nagata et al, 2002) as well as in the brain capillaries (Ohtsuki et al, 2002). In the choroid plexus, rOat3 is responsible for the uptake of PAH and PCG from the cerebrospinal fluid (Nagata et al, 2002).…”

Tubular Secretion in CKD

“…19 Because these two solutes are less well cleared than HA and CMG 25 and because their excretion variability correlates strongly with filtration, they may not represent independent secretory solutes, despite having somewhat more a priori information regarding their primary transporters. 18,26,27 They may also be subject to a high degree of protein binding, reducing availability for proximal tubule transport and thereby, possibly leading to measurement error in solute clearance.…”

Correlation of Age-Related Metabonomic Changes in 1H NMR Serum and Urine Profiles of Rats with Cognitive Function

“…HA also inhibits glucose utilization in muscles and it may be involved in development of muscular weakness [35,36]. Furthermore, it can also be correlated positively with neurophysiological indices [37], which suggest that HA induces neurological symptoms, perhaps via inhibition of organic anion transport at the blood-brain barrier or bloodcerebrospinal fluid barrier [38].…”