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Complication

Attenuation of Extracellular Matrix Accumulation in Diabetic Nephropathy by the Advanced Glycation End Product Cross-Link Breaker ALT-711 via a Protein Kinase C-α−Dependent Pathway

  1. Vicki Thallas-Bonke12,
  2. Carsten Lindschau3,
  3. Bishoy Rizkalla1,
  4. Leon A. Bach2,
  5. Geoffrey Boner14,
  6. Matthias Meier3,
  7. Hermann Haller3,
  8. Mark E. Cooper12 and
  9. Josephine M. Forbes12
  1. 1Danielle Alberti Memorial Centre for Diabetes Complications, Vascular Division, Wynn Domain, Baker Medical Research Institute, Melbourne, Australia
  2. 2Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Australia
  3. 3Department of Nephrology, Hannover Medical School, Hannover, Germany
  4. 4Department of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  1. Address correspondence and reprint requests to Vicki Thallas-Bonke, Diabetes Complications, Vascular Division, Baker Medical Research Institute, P.O. Box 6492, St. Kilda Rd. Central, Melbourne, Australia. E-mail: vicki.thallas{at}baker.edu.au
Diabetes 2004 Nov; 53(11): 2921-2930. https://doi.org/10.2337/diabetes.53.11.2921
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  • FIG. 1.
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    FIG. 1.

    Representative immunoblots stained for PKC-α (80 kDa; A), phosphorylated PKC-α (82 kDa; B), PKC-βI (80 kDa; C), PKC-βII (80 kDa; D), PKC-ε (90 kDa; E), and β-tubulin (F) in kidneys at 32 weeks.

  • FIG. 2.
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    FIG. 2.

    Representative photomicrographs of renal cortical immunostaining at 32 weeks for PKC-α in control (A), diabetic (B; arrow demonstrates cytosolic distribution), DAG (C), and DALT (D) groups, and for phosphorylated PKC-α in control (E), diabetic (F; arrow demonstrates membranous translocation), DAG (G), and DALT (H) groups. Magnification ×200.

  • FIG. 3.
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    FIG. 3.

    Representative photomicrographs of renal cortical immunostaining for PKC-βI at 32 weeks in fixed sections from control (A), diabetic (B), DAG (C), and DALT (D) groups, and in frozen sections from control (E) and diabetic (F) groups. Magnification ×200.

  • FIG. 4.
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    FIG. 4.

    A: Representative immunoblot stained for renal cortical VEGF (45 kDa) (bottom row) and β-tubulin (top row) at 32 weeks. The graph (AG) represents the densitometric analysis (means ± SE) of individual Western blots of VEGF, expressed as relative optical density (ROD). *P < 0.001 vs. control; †P < 0.001 vs. diabetic; ‡P < 0.001 for DALT vs. DAG. B: Morphometric computer-aided analysis of renal glomerular VEGF immunostaining in rats at 32 week, expressed as the percent area of the glomerulus. Data are means ± SE. *P < 0.005 vs. control; †P < 0.01 vs. diabetic; ‡P < 0.001 for DALT vs. DAG. C: Morphometric computer-aided analysis renal cortical fibronectin at 32 weeks. *P < 0.001 vs. control group; †P < 0.005 vs. diabetic group; ‡P < 0.001 vs. diabetic; §P < 0.05 for DALT vs. DAG. D: Laminin immunostaining expressed as percent area. Data are means ± SE. *P < 0.001 vs. control group; †P < 0.001 vs. diabetic group; ‡P < 0.01 for DALT vs. DAG; §P < 0.05 vs. C.

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    FIG. 5.

    A: Confocal photomicrographs of PKC-α translocation and expression showing the effects of treatment with ALT-711 and aminoguanidine (AG) on VSMCs incubated in low (5 mmol/l) and high (25 mmol/l) glucose. B: Semiquantitative analysis of immunofluorescence (>30 cells of two independent experiments) 15 h after exposure to low-glucose (LG) and high-glucose (HG) concentrations with and without treatment. Data are means ± SE. *P < 0.0001 vs. LG; †P < 0.0001 for HG vs. HG +ALT; ‡P < 0.0001 for HG + ALT vs. HG + AG.

Tables

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  • TABLE 1

    Functional and structural data from all groups

    Control groupCAG (0–32 weeks)CALT (16–32 weeks)Diabetic groupDAG (0–32 weeks)DALT (16–32 weeks)
    Plasma glucose (mmol/l)6.3 ± 0.25.9 ± 0.16.3 ± 0.128.4 ± 1.5*30.0 ± 1.4*26.9 ± 1.6*
    HbA1c (%)4.5 ± 0.24.0 ± 0.25.9 ± 0.215.2 ± 0.8*14.7 ± 0.9*15.9 ± 0.7*
    AER (mg/24 h)
        Week 161.6 (1.5−1.7)0.6 (0.5−1.5)0.9 (0.6−1.6)7.9 (4.8−21.6)*1.6 (1.0−3.1)†‡8.5 (5.7−14.5)*
        Week 323.9 (2.2−10.6)1.5 (0.6−3.2)§8.0 (3.6−9.4)59.7 (31.6−88.0)*3.4 (1.7−7.9)†21.8 (11.1−32.6)†‖
    Mean systolic blood pressure (mmHg)115 ± 5116 ± 7114 ± 6161 ± 4*142 ± 6*¶145 ± 6*¶
    Glomerular filtration rate (ml · min−1 · g kidney wt−12.2 ± 0.21.8 ± 0.22.4 ± 0.12.6 ± 0.1#2.8 ± 0.2#2.3 ± 0.2
    Kidney−to−body weight ratio (×10−3)2.9 ± 0.12.7 ± 0.22.9 ± 0.15.7 ± 0.2*5.2 ± 0.4*††5.0 ± 0.2*¶
    Renal AGEs (% area)7.7 ± 0.47.3 ± 1.68.1 ± 0.914.9 ± 0.6*8.3 ± 0.8†7.2 ± 0.7†
    • Data are means ± SE or median (interquartile range). Data for renal AGEs represent morphometric computer-aided analysis of renal cortical AGE (CML) immunostaining.

    • *

      * P < 0.001 vs control group;

    • †

      † P < 0.001 vs diabetic group;

    • ‡

      ‡ P < 0.001 for DAG vs. DALT;

    • §

      § P < 0.001 vs. CALT;

    • ¶

      ¶ P < 0.01 vs. diabetic group;

    • ‖

      ‖ P < 0.05 vs. DAG;

    • #

      # P < 0.05 vs. control group;

    • ††

      †† P < 0.05 vs. diabetic group.

  • TABLE 2

    Densitometric analysis of Western blots for PKC isoforms

    Control groupCAG (0−32 weeks)CALT (16−32 weeks)Diabetic groupDAG (0−32 weeks)DALT (16−32 weeks)
    PKC-α1.0 ± 0.11.2 ± 0.11.2 ± 0.11.8 ± 0.2*1.5 ± 0.02†1.4 ± 0.02†
    Phosphorylated PKC-α1.0 ± 0.12.1 ± 0.1*0.7 ± 0.11.8 ± 0.3*2.8 ± 0.5*1.0 ± 0.3†
    PKC-βI1.0 ± 0.10.8 ± 0.10.8 ± 0.11.7 ± 0.1*1.1 ± 0.02‡1.0 ± 0.1‡
    PKC-βII1.0 ± 0.10.7 ± 0.1§0.7 ± 0.1§1.3 ± 0.002§1.0 ± 0.1†0.9 ± 0.1†
    PKC-ε1.0 ± 0.11.2 ± 0.041.1 ± 0.11.7 ± 0.06*1.1 ± 0.04‡1.3 ± 0.1‡
    • Data are means ± SE and are expressed as relative optical density.

    • *

      * P < 0.01,

    • §

      § P < 0.05 vs. control group;

    • †

      † P < 0.05,

    • ‡

      ‡ P < 0.01 vs. diabetic group.

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Attenuation of Extracellular Matrix Accumulation in Diabetic Nephropathy by the Advanced Glycation End Product Cross-Link Breaker ALT-711 via a Protein Kinase C-α−Dependent Pathway
Vicki Thallas-Bonke, Carsten Lindschau, Bishoy Rizkalla, Leon A. Bach, Geoffrey Boner, Matthias Meier, Hermann Haller, Mark E. Cooper, Josephine M. Forbes
Diabetes Nov 2004, 53 (11) 2921-2930; DOI: 10.2337/diabetes.53.11.2921

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Attenuation of Extracellular Matrix Accumulation in Diabetic Nephropathy by the Advanced Glycation End Product Cross-Link Breaker ALT-711 via a Protein Kinase C-α−Dependent Pathway
Vicki Thallas-Bonke, Carsten Lindschau, Bishoy Rizkalla, Leon A. Bach, Geoffrey Boner, Matthias Meier, Hermann Haller, Mark E. Cooper, Josephine M. Forbes
Diabetes Nov 2004, 53 (11) 2921-2930; DOI: 10.2337/diabetes.53.11.2921
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