PPAR alpha agonists improve renal preservation in kidneys subjected to chronic in vitro perfusion: interaction with mannitol.
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.
Jackson
Travis C
TC
Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219-3130, USA.
Mi
Zaichuan
Z
Bastacky
Sheldon I
SI
McHale
Teresa
T
Melhem
Mona F
MF
Sonalker
Prajakta A
PA
Tofovic
Stevan P
SP
Jackson
Edwin K
EK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D004347:Drug Interactions; D015248:Gemfibrozil / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D008297:Male; D008353:Mannitol / Q000494:pharmacology*; D008854:Microscopy, Electron; D009926:Organ Preservation / Q000379:methods*; D047493:PPAR alpha / Q000819:agonists*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis
D047493:PPAR alpha; D008353:Mannitol; C499075:Atp1a1 protein, rat; D000254:Sodium-Potassium-Exchanging ATPase; D015248:Gemfibrozil