Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Clinical and Experimental Nephrology
Published in: Clinical and Experimental Nephrology 4/2011

01-08-2011 | Review Article

Roles of organic anion/cation transporters at the blood–brain and blood–cerebrospinal fluid barriers involving uremic toxins

Authors: Ken-ichi Hosoya, Masanori Tachikawa

Published in: Clinical and Experimental Nephrology | Issue 4/2011

Login to get access

Abstract

The blood–brain barrier (BBB) and blood–cerebrospinal fluid barrier (BCSFB) play key roles in the influx and efflux transport of endogenous substrates in the brain and cerebrospinal fluid. The organic anion transporter (OAT) 3 and organic cation transporter (OCT) 3, which belong to the solute carrier (SLC) 22A family, are expressed at the BBB and BCSFB, and regulate the excretion of endogenous and exogenous organic anions and cations. Our recent research provides novel molecular and functional evidence that indoxyl sulfate, an anionic uremic toxin, undergoes efflux transport at the BBB via OAT3 and creatinine, a uremic guanidino compound, undergoes efflux transport at the BCSFB via OCT3. Renal impairment is associated with the accumulation of uremic toxins in blood and uremic encephalopathy. It is conceivable that uremic encephalopathy is related to inhibition or dysfunction of efflux transport systems for uremic toxins in the brain. Here, we review the function of OAT3 and OCT3 at the BBB and BCSFB in the context of their roles in the progression of renal failure.
Literature
1.
Hosoya K, Ohtsuki S, Terasaki T. Recent advances in the brain-to-blood efflux transport across the blood–brain barrier. Int J Pharm. 2002;248:15–29.CrossRefPubMed
2.
Hosoya K, Hori S, Ohtsuki S, Terasaki T. A new in vitro model for blood–cerebrospinal fluid barrier transport studies: an immortalized choroid plexus epithelial cell line derived from the tsA58 SV40 large T-antigen gene transgenic rat. Adv Drug Deliv Rev. 2004;56:1875–85.CrossRefPubMed
3.
Ohtsuki S, Terasaki T. Contribution of carrier-mediated transport systems to the blood–brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development. Pharm Res. 2007;24:1745–58.CrossRefPubMed
4.
Duarte CG, Preuss HG. Assessment of renal function—glomerular and tubular. Clin Lab Med. 1993;13:33–52.CrossRefPubMed
5.
Spector R, Johanson CE. Vectorial ligand transport through mammalian choroid plexus. Pharm Res. 2010;27:2054–62.CrossRefPubMed
6.
Inui KI, Masuda S, Saito H. Cellular and molecular aspects of drug transport in the kidney. Kidney Int. 2000;58:944–58.CrossRefPubMed
7.
8.
Hagenbuch B. Drug uptake systems in liver and kidney: a historic perspective. Clin Pharmacol Ther. 2010;87:39–47.CrossRefPubMed
9.
Tachikawa M, Hosoya K. Transport characteristics of guanidino compounds at the blood–brain barrier and blood–cerebrospinal fluid barrier: relevance to neural disorders. Fluids Barriers CNS. 2011;8:13.CrossRefPubMedPubMedCentral
10.
Brouns R, De Deyn PP. Neurological complications in renal failure: a review. Clin Neurol Neurosurg. 2004;107:1–16.CrossRefPubMed
11.
Davenport A. The brain and the kidney–organ cross talk and interactions. Blood Purif. 2008;26:526–36.CrossRefPubMed
12.
Vanholder R, De Smet R, Glorieux G, Argilés A, Baurmeister U, Brunet P, Clark W, Cohen G, De Deyn PP, Deppisch R, Descamps-Latscha B, Henle T, Jörres A, Lemke HD, Massy ZA, Passlick-Deetjen J, Rodriguez M, Stegmayr B, Stenvinkel P, Tetta C, Wanner C, Zidek W. Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int. 2003;63:1934–43.CrossRefPubMed
13.
14.
Mori S, Takanaga H, Ohtsuki S, Deguchi T, Kang YS, Hosoya K, Terasaki T. Rat organic anion transporter 3 (rOAT3) is responsible for brain-to-blood efflux of homovanillic acid at the abluminal membrane of brain capillary endothelial cells. J Cereb Blood Flow Metab. 2003;23:432–40.CrossRefPubMed
15.
Sweet DH, Miller DS, Pritchard JB, Fujiwara Y, Beier DR, Nigam SK. Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J Biol Chem. 2002;277:26934–43.CrossRefPubMed
16.
Koepsell H. Organic cation transporters in intestine, kidney, liver, and brain. Annu Rev Physiol. 1998;60:243–66.CrossRefPubMed
17.
Nakayama H, Kitaichi K, Ito Y, Hashimoto K, Takagi K, Yokoi T, Takagi K, Ozaki N, Yamamoto T, Hasegawa T. The role of organic cation transporter-3 in methamphetamine disposition and its behavioral response in rats. Brain Res. 2007;1184:260–9.CrossRefPubMed
18.
Hagenbuch B, Meier PJ. The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta. 2003;1609:1–18.CrossRefPubMed
19.
Gao B, Stieger B, Noé B, Fritschy JM, Meier PJ. Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroids plexus epithelium of rat brain. J Histochem Cytochem. 1999;47:1255–64.CrossRefPubMed
20.
Ohtsuki S, Takizawa T, Takanaga H, Terasaki N, Kitazawa T, Sasaki M, Abe T, Hosoya K, Terasaki T. In vitro study of the functional expression of organic anion transporting polypeptide 3 at rat choroid plexus epithelial cells and its involvement in the cerebrospinal fluid-to-blood transport of estrone-3-sulfate. Mol Pharmacol. 2003;63:532–7.CrossRefPubMed
21.
Sugiyama D, Kusuhara H, Taniguchi H, Ishikawa S, Nozaki Y, Aburatani H, Sugiyama Y. Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood–brain barrier: high affinity transporter for thyroxine. J Biol Chem. 2003;278:43489–95.CrossRefPubMed
22.
Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 2001;11:1156–66.CrossRefPubMed
23.
Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. P-glycoprotein: from genomics to mechanism. Oncogene. 2003;22:7468–85.CrossRefPubMed
24.
de Lange EC. Potential role of ABC transporters as a detoxification system at the blood–CSF barrier. Adv Drug Deliv Rev. 2004;56:1793–809.CrossRefPubMed
25.
Leggas M, Adachi M, Scheffer GL, Sun D, Wielinga P, Du G, Mercer KE, Zhuang Y, Panetta JC, Johnston B, Scheper RJ, Stewart CF, Schuetz JD. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol Cell Biol. 2004;24:7612–21.CrossRefPubMedPubMedCentral
26.
Hori S, Ohtsuki S, Tachikawa M, Kimura N, Kondo T, Watanabe M, Nakashima E, Terasaki T. Functional expression of rat ABCG2 on the luminal side of brain capillaries and its enhancement by astrocyte-derived soluble factor(s). J Neurochem. 2004;90:526–36.CrossRefPubMed
27.
Niwa T. Uremic toxicity of indoxyl sulfate. Nagoya J Med Sci. 2010;72:1–11.PubMed
28.
Niwa T, Ise M. Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J Lab Clin Med. 1994;124:96–104.PubMed
29.
Sakai T, Maruyama T, Imamura H, Shimada H, Otagiri M. Mechanism of stereoselective serum binding of ketoprofen after hemodialysis. J Pharmacol Exp Ther. 1996;278:786–92.PubMed
30.
Enomoto A, Takeda M, Tojo A, Sekine T, Cha SH, Khamdang S, Takayama F, Aoyama I, Nakamura S, Endou H, Niwa T. Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity. J Am Soc Nephrol. 2002;13:1711–20.CrossRefPubMed
31.
Deguchi T, Ohtsuki S, Otagiri M, Takanaga H, Asaba H, Mori S, Terasaki T. Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney. Kidney Int. 2002;61:1760–8.CrossRefPubMed
32.
Deguchi T, Kusuhara H, Takadate A, Endou H, Otagiri M, Sugiyama Y. Characterization of uremic toxin transport by organic anion transporters in the kidney. Kidney Int. 2004;65:162–74.CrossRefPubMed
33.
Deguchi T, Kouno Y, Terasaki T, Takadate A, Otagiri M. Differential contributions of rOat1 (Slc22a6) and rOat3 (Slc22a8) to the in vivo renal uptake of uremic toxins in rats. Pharm Res. 2005;22:619–27.CrossRefPubMed
34.
Deguchi T, Takemoto M, Uehara N, Lindup WE, Suenaga A, Otagiri M. Renal clearance of endogenous hippurate correlates with expression levels of renal organic anion transporters in uremic rats. J Pharmacol Exp Ther. 2005;314:932–8.CrossRefPubMed
35.
Schneider R, Sauvant C, Betz B, Otremba M, Fischer D, Holzinger H, Wanner C, Galle J, Gekle M. Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats. Am J Physiol Renal Physiol. 2007;292:F1599–605.CrossRefPubMed
36.
Sakurai Y, Motohashi H, Ueo H, Masuda S, Saito H, Okuda M, Mori N, Matsuura M, Doi T, Fukatsu A, Ogawa O, Inui K. Expression levels of renal organic anion transporters (OATs) and their correlation with anionic drug excretion in patients with renal diseases. Pharm Res. 2004;21:61–7.CrossRefPubMed
37.
38.
De Deyn PP, Vanholder R, Eloot S, Glorieux G. Guanidino compounds as uremic (neuro)toxins. Semin Dial. 2009;22:340–5.CrossRefPubMed
39.
Namba S, Okuda Y, Morimoto A, Kojima T, Morita T. A serum indoxyl sulfate is a useful predictor for progression of chronic kidney disease. Rinsho Byori. 2010;58:448–53.PubMed
40.
Urakami Y, Kimura N, Okuda M, Inui K. Creatinine transport by basolateral organic cation transporter hOCT2 in the human kidney. Pharm Res. 2004;21:976–81.CrossRefPubMed
41.
Urakami Y, Kimura N, Okuda M, Masuda S, Katsura T, Inui K. Transcellular transport of creatinine in renal tubular epithelial cell line LLC-PK1. Drug Metab Pharmacokinet. 2005;20:200–5.CrossRefPubMed
42.
Müting D. Studies on the pathogenesis of uremia. Comparative determinations of glucuronic acid, indican, free and bound phenols in the serum, cerebrospinal fluid, and urine of renal diseases with and without uremia. Clin Chim Acta. 1965;12:551–4.CrossRefPubMed
43.
Kikuchi R, Kusuhara H, Sugiyama D, Sugiyama Y. Contribution of organic anion transporter 3 (Slc22a8) to the elimination of p-aminohippuric acid and benzylpenicillin across the blood–brain barrier. J Pharmacol Exp Ther. 2003;306:51–8.CrossRefPubMed
44.
Kakee A, Terasaki T, Sugiyama Y. Blood–brain barrier: in vivo evidence by use of the brain efflux index method. J Pharmacol Exp Ther. 1997;283:1018–25.PubMed
45.
Ohtsuki S, Asaba H, Takanaga H, Deguchi T, Hosoya K, Otagiri M, Terasaki T. 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. J Neurochem. 2002;83:57–66.CrossRefPubMed
46.
Deguchi T, Isozaki K, Yousuke K, Terasaki T, Otagiri M. Involvement of organic anion transporters in the efflux of uremic toxins across the blood–brain barrier. J Neurochem. 2006;96:1051–9.CrossRefPubMed
47.
Tachikawa M, Hosoya K, Ohtsuki S, Terasaki T. A novel relationship between creatine transport at the blood–brain and blood–retinal barriers, creatine biosynthesis, and its use for brain and retinal energy homeostasis. Subcell Biochem. 2007;46:83–98.CrossRefPubMed
48.
Marescau B, Deshmukh DR, Kockx M, Possemiers I, Qureshi IA, Wiechert P, De Deyn PP. Guanidino compounds in serum, urine, liver, kidney, and brain of man and some ureotelic animals. Metabolism. 1992;41:526–32.CrossRefPubMed
49.
De Deyn PP, D’Hooge R, Van Bogaert PP, Marescau B. Endogenous guanidino compounds as uremic neurotoxins. Kidney Int Suppl. 2001;78:S77–83.CrossRefPubMed
50.
Ku CP, Passow H. Creatine and creatinine transport in old and young human red blood cells. Biochim Biophys Acta. 1980;600:212–27.CrossRefPubMed
51.
Tachikawa M, Kasai Y, Takahashi M, Fujinawa J, Kitaichi K, Terasaki T, Hosoya K. The blood–cerebrospinal fluid barrier is a major pathway of cerebral creatinine clearance: involvement of transporter-mediated process. J Neurochem. 2008;107:432–42.CrossRefPubMed
52.
Hayer-Zillgen M, Brüss M, Bönisch H. Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br J Pharmacol. 2002;136:829–36.CrossRefPubMedPubMedCentral
53.
Noé B, Hagenbuch B, Stieger B, Meier PJ. Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proc Natl Acad Sci USA. 1997;94:10346–50.CrossRefPubMed
54.
Lim CF, Bernard BF, de Jong M, Docter R, Krenning EP, Hennemann G. A furan fatty acid and indoxyl sulfate are the putative inhibitors of thyroxine hepatocyte transport in uremia. J Clin Endocrinol Metab. 1993;76:318–24.PubMed
55.
Porter RD, Cathcart-Rake WF, Wan SH, Whittier FC, Grantham JJ. Secretory activity and aryl acid content of serum, urine, and cerebrospinal fluid in normal and uremic man. J Lab Clin Med. 1975;85:723–31.PubMed
56.
Sullivan PA, Murnaghan D, Callaghan N, Kantamaneni BD, Curzon G. Cerebral transmitter precursors and metabolites in advanced renal disease. J Neurol Neurosurg Psychiatry. 1978;41:581–8.CrossRefPubMedPubMedCentral
57.
Burke WJ, Li SW, Schmitt CA, Xia P, Chung HD, Gillespie KN. Accumulation of 3,4-dihydroxyphenylglycolaldehyde, the neurotoxic monoamine oxidase A metabolite of norepinephrine, in locus ceruleus cell bodies in Alzheimer’s disease: mechanism of neuron death. Brain Res. 1999;816:633–7.CrossRefPubMed
58.
Lamensdorf I, Eisenhofer G, Harvey-White J, Hayakawa Y, Kirk K, Kopin IJ. Metabolic stress in PC12 cells induces the formation of the endogenous dopaminergic neurotoxin, 3,4-dihydroxyphenylacetaldehyde. J Neurosci Res. 2000;60:552–8.CrossRefPubMed
59.
Marescau B, Nagels G, Possemiers I, De Broe ME, Becaus I, Billiouw JM, Lornoy W, De Deyn PP. Guanidino compounds in serum and urine of nondialyzed patients with chronic renal insufficiency. Metabolism. 1997;46:1024–31.CrossRefPubMed
60.
Ohtsuki S, Tomi M, Hata T, Nagai Y, Hori S, Mori S, Hosoya K, Terasaki T. Dominant expression of androgen receptors and their functional regulation of organic anion transporter 3 in rat brain capillary endothelial cells; comparison of gene expression between the blood–brain and –retinal barriers. J Cell Physiol. 2005;204:896–900.CrossRefPubMed
Metadata
Title
Roles of organic anion/cation transporters at the blood–brain and blood–cerebrospinal fluid barriers involving uremic toxins
Authors
Ken-ichi Hosoya
Masanori Tachikawa
Publication date
01-08-2011
Publisher
Springer Japan
Published in
Clinical and Experimental Nephrology / Issue 4/2011
Print ISSN: 1342-1751
Electronic ISSN: 1437-7799
DOI
https://doi.org/10.1007/s10157-011-0460-y

Other articles of this Issue 4/2011

Clinical and Experimental Nephrology 4/2011 Go to the issue

Erratum

Erratum to: Tubulointerstitial immune complex nephritis in a patient with systemic lupus erythematosus: role of peritubular capillaritis with immune complex deposits in the pathogenesis of the tubulointerstitial nephritis

Original Article

Altered monocyte-derived dendritic cell function in patients on hemodialysis: a culprit for underlying impaired immune responses

Case Report

A patient undergoing chronic dialysis whose renal anemia was successfully corrected by treatment with cinacalcet

Erratum

Erratum to: Dual myeloperoxidase-antineutrophil cytoplasmic antibody- and antiglomerular basement membrane antibody-positive cases associated with prior pulmonary fibrosis: a report of four cases

Editorial Announcement

A new journal: CEN Case Reports

Review Article

Anti-ribosomal P antibodies and lupus nephritis
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits