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- Title
PPAR α agonists improve renal preservation in kidneys subjected to chronic in vitro perfusion: interaction with mannitol.
- Authors
Jackson, Travis C.; Zaichuan Mi; Bastacky, Sheldon I.; McHale, Teresa; Melhem, Mona F.; Sonalker, Prajakta A.; Tofovic, Stevan P.; Jackson, Edwin K.
- 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 (PPAR α) 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); KATP opener (minoxidil, minoxidil sulfate); PARP inhibitor (3-aminobenzamide); calcium channel blocker (verapamil); V2 agonist (DDAVP); diuretics (acetazolamide, hydrochlorothiazide, furosemide, mannitol); peroxisome proliferator-activated receptor-beta agonist (L-165041); dopamine agonist (dopamine); essential fatty acid (linolenic acid); β-NAD; urea; uric acid; and aldosterone. In pilot studies, only PPAR α 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 °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- α1 (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 PPAR α agonists, particularly when combined with mannitol, protect organs from normothermic, perfusion-induced damage.
- Subjects
PERFUSION; KIDNEY diseases; CHRONIC kidney failure; CHEMICAL agonists; DRUG administration; ADRENERGIC beta agonists
- Publication
Transplant International, 2007, Vol 20, Issue 3, p277
- ISSN
0934-0874
- Publication type
Article
- DOI
10.1111/j.1432-2277.2006.00431.x