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Stimulating effect of indoxyl sulfate on progression of renal failure and development of an inhibitor of its production

Research Project

Project/Area Number 11557076
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section展開研究
Research Field Kidney internal medicine
Research InstitutionNAGOYA UNIVERSITY

Principal Investigator

NIWA Toshimitsu  SCHOOL OF MEDICINE, NAGOYA UNIVERSITY, ASSOCIATE PROFESSOR, 医学部, 助教授 (20208268)

Co-Investigator(Kenkyū-buntansha) 宮崎 高志  名古屋大学, 医学部, 医員
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2000: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1999: ¥9,400,000 (Direct Cost: ¥9,400,000)
Keywordsprogression of renal failure / organic anion transporter / protein metabolite theory / indoxyl sulfate / TGF-β
Research Abstract

To clarify the role of indoxyl sulfate in the progression of renal failure, the expressions of genes related to tubulointerstitial fibrosis such as TGF-b1, TIMP-1 and pro al(I) collagen were examined in the renal cortex of 5/6-nephrectomized uremic rats given indoxyl sulfate. The administration of indoxyl sulfate for 5 weeks significantly increased the mRNA levels of transforming growth factor (TGF)-β1, tissue inhibitor of metalloproteinases (TIMP)-1 and pro al(I) collagen in the uremic rats given indoxyl sulfate compared with the control uremic rats, accompanied by a significant decline in renal function and worsening of glomerular sclerosis. Thus, we hypothesized that the overload of protein metabolites such as indoxyl sulfate on nephrons promotes the progression of CRF.Further, to clarify if indoxyl sulfate administration affects the expression of organic anion transporter (OAT)-1 and OAT3 in the kidneys, indoxyl sulfate was administered to 5/6-nephrectomized uremic rats for 16 weeks. Indoxyl sulfate was localized in the proximal tubular epithelial cells, especially of dilated tubules, of the control uremic rat kidneys, and that indoxyl sulfate administration markedly increased the tubular staining of indoxyl sulfate. The administration of indoxyl sulfate further dccreased the expression of OAT1 and increased the expression of OAT3. The immunostaining of indoxyl sulfate was more intense in the OAT3-positive proximal tubules rather than in the OAT1-positive proximal tubules. In conclusion, indoxyl sulfate is excreted to urine through active uptake by OAT1 and OAT3 in the basolateral membranes of renal proximal tubules. Uremic rats, especially indoxyl sulfate-administered uremic rats, showed decreased expression of OAT1 and increased expression of OAT3. The target of nephrotoxicity of indoxyl sulfate seems to te OAT3-expressed proximal tubules.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Aoyama I: "Oral adsorbent ameliorates renal TGF-β1 expression in hypercholesterolemic rats."Kidney Int. 56(Suppl 71). S193-S197 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Niwa T: "Urinary indoxyl sulfate is a clinical factor that affects the progression of renal failure."Miner Electrol Metab. 25. 118-122 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Aoyama I: "Oral adsorbent AST-120 ameliorates interstitial fibrosis and transforming growth factor-β1 expression in spontaneously diabetic (OLETF) rats."Am J Nephrol. 20. 232-241 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miyazaki T: "An oral sorbent reduces overload of indoxyl sulfate and gene expression of TGF-β1 in uremic rat kidneys."Nephrol Dial Transplant. 15. 1773-1781 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Aoyama I: "An oral adsorbent ameliorates renal overload of indoxyl sulfate and progression of renal failure in diabetic rats."Am J Kidney Dis. 37(Suppl 2). S7-S12 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Aoyama I: "Combination therapy of benazepril and oral adsorbent ameliorates progressive renal fibrosis in uremic rats."Nephron. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Niwa T: "Textbook of Nephrology (Uremic Toxicity. Indoxyl sulfate.)"Williams & Wilkins. 1269-1272 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Aoyama I: "Oral absorbent ameliorates renal TFG-β1 expression in hypercholesterolemic rats."Kidney Int. 56 (Suppl 71). S193-S197 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Niwa T: "Urinary indoxyl sulfate is a clinical factor that affects the progression of renal failure."Miner Electrol Metab. 25. 118-122 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Aoyama I: "Oral adsorbent AST-120 ameliorates interstitial fibrosis and transforming growth factor-β1 expression in spontaneously diabetic (OLETF) rats."Am J Nephrol. 20. 232-241 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miyazaki T: "An oral sorbent reduces overload of indoxyl sulfate and gene expression of TFG-β1 in uremic rat kidneys."Nephrol Dial Transplant. 15. 1773-1781 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Aoyama I: "An oral adsorbent ameliorates renal overload of indoxyl sulfate and progression of renal failure in diabetic rats."Am J Kidney Dis. 37 (Suppl 2). S7-S12 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Aoyama I: "Combination therapy of benazepril and oral adsorbent ameliorates progressive renal fibrosis in uremic rats."Nephron. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Niwa T: "Uremic Toxicity. Indoxyl sulfate. Textbook of Nephrology (e.d. Massry SG, Glassock RJ)"Williams & Wilkins. 1269-1272 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Aoyama I: "Oral adsorbent AST-120 ameliorates interstitial fibrosis and transforming growth factor-β1 expression in spontaneously diabetic (OLETF) rats."Am J Nephrol. 20. 232-241 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miyazaki T: "An oral sorbent reduces overload of indoxyl sulfate and gene expression of TGF-β1 in uremic rat kidneys."Nephrol Dial Transplant. 15. 1773-1781 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Aoyama I: "An oral adsorbent ameliorates renal overload of indoxyl sulfate and progression of renal failure in diabetic rats."Am J Kidney Dis. 37(Suppl 2). S7-S12 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Aoyama I: "Combination therapy of benazepril and oral adsorbent ameliorates progressive renal fibrosis in uremic rats."Nephron. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Niwa T: "Textbook of Nephrology (Uremic Toxicity. Indoxyl sulfate.)"Williams & Wilkins. 1269-1272 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Aoyama I: "Oral adsorbent ameliorates renal TGF-β1 expression in hypercholesterolemic rats."Kidney Int. 56(Suppl 71). S193-S197 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Aoyama I: "Preventive effects of an oral sorbent on nephropathy in rats."Miner Electrol Metab. 25. 365-372 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Niwa T: "Urinary indoxyl sulfate is a clinical factor that affects the progression of renal failure."Miner Electrol Metab. 25. 118-122 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Miyazaki T: "An oral sorbent reduces overload of indoxyl sulfate and gene expression of TGF-β1 in uremic rat kidneys."Nephrol Dial Transplant. (in press). (2000)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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