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Complications

Reduction of the Accumulation of Advanced Glycation End Products by ACE Inhibition in Experimental Diabetic Nephropathy

  1. Josephine M. Forbes1,
  2. Mark E. Cooper1,
  3. Vicki Thallas1,
  4. Wendy C. Burns1,
  5. Merlin C. Thomas1,
  6. Gail C. Brammar1,
  7. Fiona Lee1,
  8. Sharon L. Grant1,
  9. Louise M. Burrell1,
  10. George Jerums2 and
  11. Tanya M. Osicka2
  1. 1Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, West Heidelberg, Australia
  2. 2Department of Endocrinology, Austin and Repatriation Medical Centre, Heidelberg, Australia
Diabetes 2002 Nov; 51(11): 3274-3282.
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  • FIG. 1.
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    FIG. 1.

    Albumin excretion over 24 h at week 12. Data are expressed as geometric mean ×/÷ tolerance factor. *P < 0.005 vs. control; †P < 0.001, ‡P < 0.05 vs. diabetic. Cont, control; C+ACEi, control plus ACEI; C+AG, control plus aminoguanidine; Diab, diabetic; D+ACEi, diabetic plus ACEI; D+AG, diabetic plus aminoguanidine.

  • FIG. 2.
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    FIG. 2.

    A: Renal AGE fluorescence at 370/440 nm corrected for protein content. *P < 0.001 vs. diabetic; †P < 0.05 vs. control. B: Morphometric analysis of immunostaining for renal AGEs. *P < 0.001 for control vs. diabetic; †P < 0.01 vs. diabetic. C, control; C+ACEi, control plus ACEI; C+AG, control plus aminoguanidine; D, diabetic; D+ACEi, diabetic plus ACEI; D+AG, diabetic plus aminoguanidine.

  • FIG. 3.
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    FIG. 3.

    Immunohistochemical staining for renal AGEs at week 12. A: Control kidney; B: Diabetic kidney; C: Diabetic kidney plus ACE inhibition; D: negative control kidney. Magnification ×400.

  • FIG. 4.
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    FIG. 4.

    Morphometric analysis of immunostaining for renal RAGE at week 12. *P < 0.001 vs. control; †P = 0.07 vs. diabetic. Cont, control; C+ACEi, control plus ACEI; C+AG, control plus aminoguanidine; Diab, diabetic; D+ACEi, diabetic plus ACEI; D+AG, diabetic plus aminoguanidine.

  • FIG. 5.
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    FIG. 5.

    A: Morphometric analysis of immunostaining for glomerular nitrotyrosine at week 12. *P < 0.005 vs. control; †P < 0.001 vs. diabetic. B: Morphometric analysis of immunostaining for tubular nitrotyrosine at week 12. *P < 0.001 vs. diabetic; †P < 0.001 vs. control; ‡P < 0.01 vs. control plus ACEI. Cont, control; C+ACEi, control plus ACEI; C+AG, control plus aminoguanidine; Diab, diabetic; D+ACEi, diabetic plus ACEI; D+AG, diabetic plus aminoguanidine.

  • FIG. 6.
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    FIG. 6.

    Immunohistochemical staining for renal nitrotyrosine (A), control kidney (B), diabetic kidney (C), and diabetic kidney plus ACE inhibition (D). Magnification ×400.

  • FIG. 7.
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    FIG. 7.

    A: Representative EMSA acrylamide gel pictured for all groups at 12 weeks. B: Quantitation of activated NF-κB by EMSA. *P < 0.05 vs. control group. Cont, control; Diab, diabetic; C+AG, control plus aminoguanidine; D+AG, diabetic plus aminoguanidine; C+ACEi, control plus ACEI; D+ACEi, diabetic plus ACEI.

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    Biochemical and metabolic parameters for all animals at week 12

    ControlControl plus ACEIControl plus AGDiabeticDiabetic plus ACEIDiabetic plus AG
    n666666
    Glucose (mmol/l)5.4 ± 0.25.8 ± 0.25.6 ± 0.222.1 ± 1.7*18.4 ± 2.0*21.4 ± 1.5*
    HbA1c (%)3.6 ± 0.23.3 ± 0.63.9 ± 0.210.6 ± 0.4*9.1 ± 0.7*9.7 ± 0.5*
    Body weight (g)453 ± 8402 ± 17420 ± 12302 ± 15*314 ± 22*341 ± 22*
    Kidney-to-body weight ratio (×10−3)6.4 ± 0.37.1 ± 0.26.6 ± 0.110.7 ± 0.4*10.0 ± 0.0*10.7 ± 0.0*
    GFR (ml/min)3.2 ± 0.23.3 ± 0.23.2 ± 0.13.9 ± 0.2†3.5 ± 0.34.1 ± 0.2*
    Urine volume (ml/24 h)15 ± 122 ± 225 ± 2121 ± 12*76 ± 14*107 ± 16*
    Blood pressure (mmHg)133 ± 3130 ± 7140 ± 5147 ± 3129 ± 7‡144 ± 5
    Serum AGEs8.7 ± 0.68.3 ± 0.67.7 ± 0.611.6 ± 0.4*8.3 ± 0.6‡8.7 ± 0.5‡
    • * P < 0.005;

    • † P < 0.02 vs. appropriate control;

    • ‡ P < 0.05 vs. diabetic. AG, aminoguanidine.

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Reduction of the Accumulation of Advanced Glycation End Products by ACE Inhibition in Experimental Diabetic Nephropathy
Josephine M. Forbes, Mark E. Cooper, Vicki Thallas, Wendy C. Burns, Merlin C. Thomas, Gail C. Brammar, Fiona Lee, Sharon L. Grant, Louise M. Burrell, George Jerums, Tanya M. Osicka
Diabetes Nov 2002, 51 (11) 3274-3282;

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Reduction of the Accumulation of Advanced Glycation End Products by ACE Inhibition in Experimental Diabetic Nephropathy
Josephine M. Forbes, Mark E. Cooper, Vicki Thallas, Wendy C. Burns, Merlin C. Thomas, Gail C. Brammar, Fiona Lee, Sharon L. Grant, Louise M. Burrell, George Jerums, Tanya M. Osicka
Diabetes Nov 2002, 51 (11) 3274-3282;
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