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  • Title: AGE formation blockade with aminoguanidine does not ameliorate chronic allograft nephropathy.
    Author: Schmaderer C, Xing CJ, Anderson G, Hermans R, Lutz J, Heemann U, Baumann M.
    Journal: Life Sci; 2011 Sep 12; 89(11-12):349-54. PubMed ID: 21763321.
    Abstract:
    AIMS: Advanced glycation end products (AGEs) are produced by glycoxidation and lipid peroxidation. AGEs induce oxidative stress and inflammation, and accumulate in tubular cells after kidney transplantation. We hypothesize that the AGE formation blocker aminoguanidine (AG) reduces AGE formation and improves renal transplant function. MAIN METHODS: Fisher 344 kidneys were orthotopically transplanted into Lewis recipients. Recipients were treated with AG (100 mg/kg/day), candesartan (CAND; 5mg/kg/day), or vehicle (VEH) for 24 weeks. The major non-cross linking AGE N(ε)-carboxymethyllysine (CML) was measured post-transplantation with gas chromatography-tandem mass spectrometry or immunohistochemistry. As a marker of systemic lipid peroxidation 8-isoprostane was measured by ELISA. We determined intra-arterial blood pressure, heart weight/body weight ratio, size of cardiomyocytes and cardiac hypertrophy as assessed by echocardiography. For biochemical evaluation of cardiac and renal fibrosis we measured hydroxyproline content. KEY FINDINGS: AG significantly reduced serum CML and 8-isoprostane, but did not reduce signs of chronic allograft nephropathy (CAN) or blood pressure. AG did not alter tubular AGE accumulation. AG reduced heart weight/body weight ratio (AG: 2.7 ± 0.1g/kg; CAND: 2.2 ± 0.1, VEH: 3.0 ± 0.4 g/kg), size of cardiomyocytes (P < 0.05) and showed a tendency to reduce cardiac hypertrophy (wall volume average radial AG 7.072 ± 0.83 cm(3) vs. CAND 6.841 ± 0.66 cm(3) vs. VEH 7.839 ± 0.74 cm(3)). SIGNIFICANCE: Despite effective reduction of serum CML and 8-isoprostane, AG did not ameliorate CAN or reduce renal AGE accumulation. On the other hand AG reduced cardiac size suggesting a supportive cardio-protective action which is blood pressure independent.
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