Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review Article
  • Published:
Clinical and Experimental Nephrology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  4. Duarte CG, Preuss HG. Assessment of renal function—glomerular and tubular. Clin Lab Med. 1993;13:33–52.

    Article  CAS  PubMed  Google Scholar 

  5. Spector R, Johanson CE. Vectorial ligand transport through mammalian choroid plexus. Pharm Res. 2010;27:2054–62.

    Article  CAS  PubMed  Google Scholar 

  6. Inui KI, Masuda S, Saito H. Cellular and molecular aspects of drug transport in the kidney. Kidney Int. 2000;58:944–58.

    Article  CAS  PubMed  Google Scholar 

  7. Tsuji A, Tamai I. Carrier-mediated intestinal transport of drugs. Pharm Res. 1996;13:963–77.

    Article  CAS  PubMed  Google Scholar 

  8. Hagenbuch B. Drug uptake systems in liver and kidney: a historic perspective. Clin Pharmacol Ther. 2010;87:39–47.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Brouns R, De Deyn PP. Neurological complications in renal failure: a review. Clin Neurol Neurosurg. 2004;107:1–16.

    Article  CAS  PubMed  Google Scholar 

  11. Davenport A. The brain and the kidney–organ cross talk and interactions. Blood Purif. 2008;26:526–36.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  13. Koepsell H, Endou H. The SLC22 drug transporter family. Pflugers Arch. 2004;447:666–76.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  16. Koepsell H. Organic cation transporters in intestine, kidney, liver, and brain. Annu Rev Physiol. 1998;60:243–66.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  18. Hagenbuch B, Meier PJ. The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta. 2003;1609:1–18.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  22. Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 2001;11:1156–66.

    Article  CAS  PubMed  Google Scholar 

  23. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. P-glycoprotein: from genomics to mechanism. Oncogene. 2003;22:7468–85.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  27. Niwa T. Uremic toxicity of indoxyl sulfate. Nagoya J Med Sci. 2010;72:1–11.

    PubMed  CAS  Google Scholar 

  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  CAS  Google Scholar 

  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  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  37. Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev. 2000;80:1107–213.

    Article  CAS  PubMed  Google Scholar 

  38. De Deyn PP, Vanholder R, Eloot S, Glorieux G. Guanidino compounds as uremic (neuro)toxins. Semin Dial. 2009;22:340–5.

    Article  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  50. Ku CP, Passow H. Creatine and creatinine transport in old and young human red blood cells. Biochim Biophys Acta. 1980;600:212–27.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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  CAS  Google Scholar 

  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  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Unfortunately we could not list all the contributors and original papers involving efflux transport of uremic toxins. However, we would especially like to acknowledge the collaboration of Drs. T. Terasaki (Tohoku University) and M. Otagiri (Kumamoto University). This work was supported, in part, by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630, Sugitani, Toyama, 930-0194, Japan

    Ken-ichi Hosoya & Masanori Tachikawa

Authors
  1. Ken-ichi Hosoya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masanori Tachikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ken-ichi Hosoya.

About this article

Cite this article

Hosoya, Ki., Tachikawa, M. Roles of organic anion/cation transporters at the blood–brain and blood–cerebrospinal fluid barriers involving uremic toxins. Clin Exp Nephrol 15, 478–485 (2011). https://doi.org/10.1007/s10157-011-0460-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10157-011-0460-y

Keywords

Search

Navigation