Article

PPARα agonists improve renal preservation in kidneys subjected to chronic in vitro perfusion: Interaction with mannitol

University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Transplant International (Impact Factor: 2.6). 04/2007; 20(3):277-90. DOI: 10.1111/j.1432-2277.2006.00431.x
Source: PubMed

ABSTRACT

We developed methods for prolonged (12 h), sterile, normothermic perfusion of rat kidneys and screened compounds for renal preservation including: mitochondrial transition pore inhibitor (decylubiquinone); caspase inhibitor (Z-VAD); peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists (gemfibrozil, WY-14643); antioxidants (trolox, luteolin, quercetin); growth factors (HGF, PDGF, EGF, IGF-1, VEGF, transferrin); calpain inhibitor (Z-Val-Phe-CHO); calmodulin inhibitor (W7); K(ATP) opener (minoxidil, minoxidil sulfate); PARP inhibitor (3-aminobenzamide); calcium channel blocker (verapamil); V(2) agonist (DDAVP); diuretics (acetazolamide, hydrochlorothiazide, furosemide, mannitol); peroxisome proliferator-activated receptor-beta agonist (L-165041); dopamine agonist (dopamine); essential fatty acid (linolenic acid); beta-NAD; urea; uric acid; and aldosterone. In pilot studies, only PPARalpha agonists and mannitol provided promising results. Accordingly, these agents were investigated further. Fifteen rat kidneys were perfused for 12 h with L-15 media at 37 degrees C in the absence or presence of mannitol, gemfibrozil, gemfibrozil + mannitol or WY-14643. Chronic perfusion in untreated kidneys caused destruction of glomerular and tubular architecture (light and electron microscopy), disappearance of Na(+)-K(+)-ATPase-alpha(1) (Western blotting), and apoptosis (Apoptag staining). Gemfibrozil and WY-14643 marginally improved some biomarkers of renal preservation. However, the combination of gemfibrozil with mannitol markedly improved all parameters of renal preservation. We conclude that PPARalpha agonists, particularly when combined with mannitol, protect organs from normothermic, perfusion-induced damage.

Download full-text

Full-text

Available from: Edwin K Jackson, Oct 04, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are therapeutic targets for fibrates and thiazolidinediones, which are commonly used to ameliorate hyperlipidemia and hyperglycemia in type 2 diabetes. In this study, we evaluated whether activation of PPAR alpha and PPAR gamma stimulates neoangiogenesis. We used selective synthetic PPAR alpha and PPAR gamma agonists and investigated their angiogenic potentials in vitro and in vivo. Activation of PPAR alpha and PPAR gamma leads to endothelial tube formation in an endothelial/interstitial cell co-culture assay. This effect is associated with increased production of the angiogenic cytokine vascular endothelial growth factor (VEGF). Neovascularization also occurs in vivo, when PPAR alpha and PPAR gamma agonists are used in the murine corneal angiogenic model. No vascular growth is detectable when PPAR alpha and PPAR gamma agonists are respectively used in PPAR alpha knockout mice and mice treated with a specific PPAR gamma inhibitor, demonstrating that this angiogenic response is PPAR mediated. PPAR alpha- and PPAR gamma-induced angiogenesis is associated with local VEGF production and does not differ in extent and morphology from that induced by VEGF. In addition, PPAR alpha- and PPAR gamma-induced in vitro and in vivo angiogenesis may be significantly decreased by inhibiting VEGF activity. Finally, in corneas treated with PPAR alpha and PPAR gamma agonists, there is increased phosphorylation of endothelial nitric oxide synthase and Akt. These findings demonstrate that PPAR alpha and PPAR gamma activation stimulates neoangiogenesis through a VEGF-dependent mechanism. Neoangiogenesis is a crucial pathological event in type 2 diabetes. The ability of PPAR alpha and PPAR gamma agonists to induce neoangiogenesis might have important implications for the clinical and therapeutic management of type 2 diabetes.
    Full-text · Article · Jun 2008 · Diabetes
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim: A multiple-dose pharmacokinetic-pharmacodynamic model was proposed to study the relationship between pharmacokinetic profile and insulin sensitivity index of telmisartan. Methods: Model of insulin-resistance was developed by feeding high-fat and high-fructose diet to SD rats in two successive months. The insulin-resistance rats were then randomly divided into telmisartan(4 mg/ (kg ·day)), telmisartan(8 mg/(kg · day)) and control groups. The insulin-resistance rats received repeated gastric dosing of telmisartan in 45 days. The rat plasma samples were collected at predetermined intervals, and determined for telmisartan blood levels. Meanwhile, rat blood glucose and blood insulin levels were determined before dosing and at days 9, 18, 27, 36, and 45 after dosing. Insulin sensitivity index was used as the quantitative parameter for measuring the efficacy. The relationship of drug exposure to insulin sensitivity index was modeled by the suggested pharmacokinetic-pharmacodynamic model. Results: There was no considerable telmisartan accumulation in the rats after oral multiple-dosing administration. No significant difference in the pharmacokinetic parameters between the first and the final administration was found. AUC50 of insulin sensitivity index at 4 mg/ (kg · day) and 8 mg/(kg · day) were 2 886.0 ng ·day/mL and 3 218.9 ng · day/mL, respectively. Conclusion: Our results indicates that there is a long and slow period in the improvement of telmisartan to insulin resistance and that this effect is well correlated with the drug exposure index instead of drug concentration.
    No preview · Article · Oct 2008 · Journal of China Pharmaceutical University
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gemfibrozil is long known for its ability to reduce the level of triglycerides in the blood circulation and to decrease the risk of hyperlipidemia. However, a number of recent studies reveal that apart from its lipid-lowering effects, gemfibrozil can also regulate many other signaling pathways responsible for inflammation, switching of T-helper cells, cell-to-cell contact, migration, and oxidative stress. In this review, we have made an honest attempt to analyze various biological activities of gemfibrozil and associated mechanisms that may help to consider this drug for different human disorders as primary or adjunct therapy.
    Preview · Article · Feb 2009 · Immunopharmacology and Immunotoxicology
Show more