Skip to main content
SpringerLink
Log in

Toxico-Pathological Role of Hepatic Sulfotransferase (SULT) 1A1 in Acute Kidney Injuries

  • Chapter
  • First Online:
Uremic Toxins and Organ Failure

  • 225 Accesses

Abstract

Upon acute kidney injury, the renal excretion activity of indoxyl sulfate (IS) is significantly reduced because the expression of the proximal tubule-localized organic anion transporters Oat1 and Oat3 that mediate urinary excretion of IS is markedly downregulated. The downregulation response of both these transporters is commonly observed in ischemic nephropathy and cisplatin-induced nephropathy. In mice deficient in Sulfotransferase (SULT) 1A1 that mediates production of IS in the liver, the accumulation of IS in serum and kidney tissue is reduced with a marked decrease in IS production, resulting in suppression of renal dysfunction. IS accumulates throughout the kidney tissue and is closely involved in the progression of renal injury through the production of oxidative stress. In cisplatin-induced acute kidney injury, it was found that IS acts as a ligand to the aryl hydrocarbon receptor and thereby induces oxidative stress by enhancing the expression of xanthine oxidase present in the downstream region. Selective inhibitors targeting hepatic SULT1A1 could suppress the production of IS in the liver with the reduced exacerbation of kidney damage, suggesting that SULT1A1 could be potential as a novel therapeutic target for inhibiting uremic toxin accumulation in organs.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Vanholder R, De Smet R, Glorieux G, Argilés A, Baurmeister U, Brunet P, et al. Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int. 2003;63:1934–43.

    Article  CAS  PubMed  Google Scholar 

  2. Niwa T, Ise M. Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J Lab Clin Med. 1994;124:96–104.

    CAS  PubMed  Google Scholar 

  3. Niwa T. Indoxyl sulfate is a nephro-vascular toxin. J Ren Nutr. 2010;20:S2–6.

    Article  CAS  PubMed  Google Scholar 

  4. Niwa T. Role of indoxyl sulfate in the progression of chronic kidney disease and cardiovascular disease: experimental and clinical effects of oral sorbent AST-120. Ther Apher Dial. 2011;15:120–4.

    Article  CAS  PubMed  Google Scholar 

  5. Niwa T. Update of uremic toxin research by mass spectrometry. Mass Spectrom Rev. 2011;3:510–21.

    Article  CAS  Google Scholar 

  6. Neirynck N, Vanholder R, Schepers E, Eloot S, Pletinck A, Glorieux G. An update on uremic toxins. Int Urol Nephrol. 2013;45:139–50.

    Article  CAS  PubMed  Google Scholar 

  7. Banoglu E, Jha GG, King RS. Hepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate. Eur J Drug Metab Pharmacokinet. 2001;26:235–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Banoglu E, King RS. Sulfation of indoxyl by human and rat aryl (phenol) sulfotransferases to form indoxyl sulfate. Eur J Drug Meta Pharmacokinet. 2002;27:135–40.

    Article  CAS  Google Scholar 

  9. Enomoto A, Takeda M, Tojo A, Sekine T, Cha SH, Khamdang S, et al. 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 

  10. Matsuzaki T, Watanabe H, Yoshitome K, Morisaki T, Hamada A, Nonoguchi H, et al. Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute renal failure. Kidney Int. 2007;71:539–47.

    Article  CAS  PubMed  Google Scholar 

  11. Morisaki T, Matsuzaki T, Yokoo K, Kusumoto M, Iwata K, Hamada A, et al. Regulation of renal organic ion transporters in cisplatin-induced acute kidney injury and uremia in rats. Pharm Res. 2008;25:2526–33.

    Article  CAS  PubMed  Google Scholar 

  12. Kusumoto M, Kamobayashi H, Sato D, Komori M, Yoshimura M, Hamada A, et al. Alleviation of cisplatin-induced acute kidney injury using phytochemical polyphenols is accompanied by reduced accumulation of indoxyl sulfate in rats. Clin Exp Nephrol. 2011;15:820–30.

    Article  CAS  PubMed  Google Scholar 

  13. Saito H, Yoshimura M, Saigo C, Komori M, Nomura Y, Yamamoto Y, et al. Hepatic sulfotransferase as a nephropreventing target by suppression of the uremic toxin indoxyl sulfate accumulation in ischemic acute kidney injury. Toxicol Sci. 2014;141:206–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bonventre JV, Yang L. Kidney injury molecule-1. Curr Opin Crit Care. 2010;16:556–61.

    Article  PubMed  Google Scholar 

  15. Wu L, Zhang Y, Ma X, Zhang N, Qin G. The effect of resveratrol on FoxO1 expression in kidneys of diabetic nephropathy rats. Mol Biol Rep. 2012;39:9085–93.

    Article  CAS  PubMed  Google Scholar 

  16. Ara C, Karabulut AB, Kirimlioglu H, Coban S, Ugras M, Kirimliglu V, et al. Protective effect of resveratrol against renal oxidative stress in cholestasis. Ren Fail. 2005;27:435–40.

    Article  CAS  PubMed  Google Scholar 

  17. Saito H. Toxico-pharmacological perspective of the Nrf2-Keap1 defense system against oxidative stress in kidney diseases. Biochem Pharmacol. 2013;85:865–72.

    Article  CAS  PubMed  Google Scholar 

  18. Kumar A, Singh CK, Lavoie HA, Dipette DJ, Singh US. Resveratrol restores Nrf2 level and prevents ethanol-induced toxic effects in the cerebellum of a rodent model of fetal alcohol spectrum disorders. Mol Pharmacol. 2011;80:446–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Palsamy P, Subramanian S. Resveratrol protects diabetic kidney by attenuating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via Nrf2-Keap1 signaling. Biochim Biophys Acta. 1812;2011:719–31.

    Google Scholar 

  20. Saito H. Pathophysiological regulation of renal SLC22A organic ion transporters in acute kidney injury: pharmacological and toxicological implications. Pharmacol Ther. 2010;125:79–91.

    Article  CAS  PubMed  Google Scholar 

  21. Schneider R, Sauvant C, Betz B, Otremba M, Fischer D, Holzinger H, et al. 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 

  22. Shneider R, Meusel M, Renker S, Bauer C, Holzinger H, Roeder M, et al. Low-dose indomethacin after ischemic acute kidney injury prevents downregulation of Oat1/3 and improves renal outcome. Am J Physiol Renal Physiol. 2009;297:F1614–21.

    Article  CAS  Google Scholar 

  23. Lekawanvijit S, Kompa AR, Wang BH, Kelly DJ, Krum H. Cardiorenal syndrome: the emerging role of protein-bound uremic toxins. Circ Res. 2012;111:1470–83.

    Article  CAS  PubMed  Google Scholar 

  24. Lekawanvijit S, Kompa AR, Manabe M, Wang BH, Langham RG, Nishijima F, et al. Chronic kidney disease-induced cardiac fibrosis is ameliorated by reducing circulating levels of a non-dialysable uremic toxin, indoxyl sulfate. PLoS One. 2012;7:e41281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Goto S, Kitamura K, Kono K, Nakai K, Fujii H, Nishi S. Association between AST-120 and abdominal aortic calcification in predialysis patients with chronic kidney disease. Clin Exp Nephrol. 2013;17:365–71.

    Article  CAS  PubMed  Google Scholar 

  26. Saigo C, Nomura Y, Yamamoto Y, Sagata M, Matsunaga R, Jono H, et al. Meclofenamate elicits a nephropreventing effect in a rat model of ischemic acute kidney injury by suppressing indoxyl sulfate production and restoring renal organic anion transporters. Drug Des Devel Ther. 2014;8:1073–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Taguchi T, Nazneen A, Abid MR, Razzaque MS. Cisplatin-associated nephrotoxicity and pathological events. Contrib Nephrol. 2005;148:107–21.

    Article  CAS  PubMed  Google Scholar 

  28. Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: a review. Am J Med Sci. 2007;334:115–24.

    Article  PubMed  Google Scholar 

  29. Kuhlmann MK, Horsch E, Burkhardt G, Wagner M, Köhler H. Reduction of cisplatin toxicity in cultured renal tubular cells by the bioflavonoid quercetin. Arch Toxicol. 1998;72:536–40.

    Article  CAS  PubMed  Google Scholar 

  30. Behling EB, Sendão MC, Francescato HD, Antunes LM, Costa RS, Bianchi ML. Comparative study of multiple dosage of quercetin against cisplatin-induced nephrotoxicity and oxidative stress in rat kidneys. Pharmacol Rep. 2006;58:526–32.

    CAS  PubMed  Google Scholar 

  31. Do Amaral CL, Francescato HD, Coimbra TM, Costa RS, Darin JD, Antunes LM, et al. Resveratrol attenuates cisplatin-induced nephrotoxicity in rats. Arch Toxicol. 2008;82:363–70.

    Article  PubMed  CAS  Google Scholar 

  32. Baek SM, Kwon CH, Kim JH, Woo JS, Jung JS, Kim YK. Differential roles of hydrogen peroxide and hydroxyl radical in cisplatin-induced cell death in renal proximal tubular epithelial cells. Lab Clin Med. 2003;142:178–86.

    Article  CAS  Google Scholar 

  33. Hasegawa K, Wakino S, Yoshioka K, Tatematsu S, Hara Y, Minakuchi H, et al. Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function. J Biol Chem. 2010;285:13045–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Iwata K, Watanabe H, Morisaki T, Matsuzaki T, Ohmura T, Hamada A, et al. Involvement of indoxyl sulfate in renal and central nervous system toxicities during cisplatin-induced acute renal failure. Pharm Res. 2007;24:662–71.

    Article  CAS  PubMed  Google Scholar 

  35. Motojima M, Hosokawa A, Yamato H, Muraki T, Yoshioka T. Uraemic toxins induce proximal tubular injury via organic anion transporter 1-mediated uptake. Br J Pharmacol. 2002;135:555–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gelasco AK, Raymond JR. Indoxyl sulfate induces complex redox alterations in mesangial cells. Am J Physiol Renal Physiol. 2006;290:F1551–8.

    Article  CAS  PubMed  Google Scholar 

  37. Muteliefu G, Enomoto A, Jiang P, Takahashi M, Niwa T. Indoxyl sulphate induces oxidative stress and the expression of osteoblastspecific proteins in vascular smooth muscle cells. Nephrol Dial Transplant. 2009;24:2051–8.

    Article  CAS  PubMed  Google Scholar 

  38. Shimoishi K, Anraku M, Kitamura K, Tasaki Y, Taguchi K, Hashimoto M, et al. An oral adsorbent, AST-120 protects against the progression of oxidative stress by reducing the accumulation of indoxyl sulfate in the systemic circulation in renal failure. Pharm Res. 2007;24:1283–9.

    Article  CAS  PubMed  Google Scholar 

  39. Miyazaki T, Ise M, Seo H, Niwa T. Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys. Kidney Int Suppl. 1997;62:S15–22.

    CAS  PubMed  Google Scholar 

  40. Miyazaki T, Ise M, Hirata M, Endo K, Ito Y, Seo H, et al. Indoxyl sulfate stimulates renal synthesis of transforming growth factor beta 1 and progression of renal failure. Kidney Int Suppl. 1997;63:S211–4.

    CAS  PubMed  Google Scholar 

  41. Motojima M, Hosokawa A, Yamato H, Muraki T, Yoshioka T. Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in proximal tubular cells. Kidney Int. 2003;63:1671–80.

    Article  CAS  PubMed  Google Scholar 

  42. Shimizu H, Hirose Y, Nishijima F, Tsubakihara Y, Miyazaki H. ROS and PDGF-beta receptors are critically involved in indoxyl sulfate actions that promote vascular smooth muscle cell proliferation and migration. Am J Physiol Cell Physiol. 2009;297:C389–96.

    Article  CAS  PubMed  Google Scholar 

  43. Dou L, Jourde-Chiche N, Faure V, Cerini C, Berland Y, DignatGeorge F, et al. The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells. J Thromb Haemost. 2007;5:1302–8.

    Article  CAS  PubMed  Google Scholar 

  44. Dou L, Bertrand E, Cerini C, Faure V, Sampol J, Vanholder R, et al. The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair. Kidney Int. 2004;65:442–51.

    Article  CAS  PubMed  Google Scholar 

  45. Faure V, Dou L, Sabatier F, Cerini C, Sampol J, Berland Y, et al. Elevation of circulating endothelial microparticles in patients with chronic renal failure. J Thromb Haemost. 2006;4:566–73.

    Article  CAS  PubMed  Google Scholar 

  46. Lekawanvijit S, Adrahtas A, Kelly DJ, Kompa AR, Wang BH, Krum H. Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes? Eur Heart J. 2010;31:1771–9.

    Article  CAS  PubMed  Google Scholar 

  47. Adijiang A, Goto S, Uramoto S, Nishijima F, Niwa T. Indoxyl sulphate promotes aortic calcification with expression of osteoblast-specific proteins in hypertensive rats. Nephrol Dial Transplant. 2008;23:1892–901.

    Article  CAS  PubMed  Google Scholar 

  48. Taki K, Tsuruta Y, Niwa T. Indoxyl sulfate and atherosclerotic risk factors in hemodialysis patients. Am J Nephrol. 2007;27:30–5.

    Article  CAS  PubMed  Google Scholar 

  49. Barreto FC, Barreto DV, Liabeuf S, Meert N, Glorieux G, Temmar M, et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol. 2009;4:1551–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sekura RD, Jakoby WB. Phenol sulfotransferases. J Biol Chem. 1979;254:5658–63.

    CAS  PubMed  Google Scholar 

  51. Raftogianis RB. Phenol sulfotransferase pharmacogenetics in humans: association of common SULT1A1 alleles with TS PST phenotype. Biochem Biophys Res Commun. 1997;239:298–4.

    Article  CAS  PubMed  Google Scholar 

  52. Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci. 2016;73:3221–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Vriend J, Reiter RJ. The Keap1-Nrf2-antioxidant response element pathway: a review of its regulation by melatonin and the proteasome. Mol Cell Endocrinol. 2015;401:213–20.

    Article  CAS  PubMed  Google Scholar 

  54. Kamiński T, Michałowska M, Pawlak D. Aryl hydrocarbon receptor (AhR) and its endogenous agonist - indoxyl sulfate in chronic kidney disease. Postepy Hig Med Dosw. 2017;71:624–32.

    Article  Google Scholar 

  55. Kim HY, Yoo TH, Cho JY, Kim HC, Lee WW. Indoxyl sulfate-induced TNF-α is regulated by crosstalk between the aryl hydrocarbon receptor, NF-κB, and SOCS2 in human macrophages. FASEB J. 2019;33:10844–58.

    Article  CAS  PubMed  Google Scholar 

  56. Dou L, Poitevin S, Sallée M, Addi T, Gondouin B, McKay N, et al. Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease. Kidney Int. 2018;93:986–99.

    Article  CAS  PubMed  Google Scholar 

  57. Brito JS, Borges NA, Esgalhado M, Magliano DC, Soulage CO, Mafra D. Aryl hydrocarbon receptor activation in chronic kidney disease: role of uremic toxins. Nephron. 2017;137:1–7.

    Article  CAS  PubMed  Google Scholar 

  58. Swanson HI, Bradfield CA. The AH-receptor: genetics, structure and function. Pharmacogenetics. 1993;3:213–30.

    Article  CAS  PubMed  Google Scholar 

  59. Vondráček J, Machala M. Environmental ligands of the aryl hydrocarbon receptor and their effects in models of adult liver progenitor cells. Stem Cells Int. 2016;2016:4326194.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Hankinson O. The aryl hydrocarbon receptor complex. Annu Rev Pharmacol Toxicol. 1995;35:307–40.

    Article  CAS  PubMed  Google Scholar 

  61. Gondouin B, Cerini C, Dou L, Sallée M, Duval-Sabatier A, Pletinck A, et al. Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway. Kidney Int. 2013;84:733–44.

    Article  CAS  PubMed  Google Scholar 

  62. Soshilov AA, Denison MS. Ligand promiscuity of aryl hydrocarbon receptor agonists and antagonists revealed by site-directed mutagenesis. Mol Cell Biol. 2014;34:1707–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy, Kumamoto University Hospital, Kumamoto University, Kumamoto, Japan

    Hideyuki Saito

  2. Department of Clinical Pharmaceutical Sciences, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan

    Hideyuki Saito

Authors
  1. Hideyuki Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hideyuki Saito .

Editor information

Editors and Affiliations

  1. Department of Pharmacy, Kumamoto University Hospital, Kumamoto University, Kumamoto, Japan

    Hideyuki Saito

  2. Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan

    Takaaki Abe

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Saito, H. (2020). Toxico-Pathological Role of Hepatic Sulfotransferase (SULT) 1A1 in Acute Kidney Injuries. In: Saito, H., Abe, T. (eds) Uremic Toxins and Organ Failure. Springer, Singapore. https://doi.org/10.1007/978-981-15-7793-2_10

Download citation

  • DOI: https://doi.org/10.1007/978-981-15-7793-2_10

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-15-7792-5

  • Online ISBN: 978-981-15-7793-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation