PPAR? agonists improve renal preservation in kidneys subjected to chronic in vitro perfusion: interaction with mannitol

Abstract

Summary 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 (PPARα) 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 PPARα 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 PPARα agonists, particularly when combined with mannitol, protect organs from normothermic, perfusion‐induced damage.

Selective Activation of Peroxisome Proliferator–Activated Receptor (PPAR)α and PPARγ Induces Neoangiogenesis Through a Vascular Endothelial Growth Factor–Dependent Mechanism

“…These negative effects might contribute to the recently reported potential adverse cardiovascular effects of rosiglitazone in type 2 diabetes (54). Similarly, some clinical activities of fibrates, such as preservation of renal function and amelioration of endothelial dysfunction (55,56), might be partially explained by PPAR␣-induced angiogenesis and VEGF production. In conclusion, we used selective synthetic agonists of PPAR␣ and PPAR␥ and demonstrated that the stimulation of these nuclear receptors results in the activation of a strong neoangiogenic process in vitro and in vivo.…”

Gemfibrozil, stretching arms beyond lipid lowering

“…The activation of NF-κB and COX-2 enzymic activity is often correlated with the disease severity of RA. Fibrate groups of drugs inhibit the expression of COX-2 and prostaglandin synthesis by interfering NF-κB activation [54]. Furthermore, gemfibrozil, known to switch Th1 to Th2 (14), may also lower the burden of Th1 cytokines in RA.…”

Cross-talk between heme oxygenase and peroxisome proliferator-activated receptors in the regulation of physiological functions

“…At extracellular level, PPAR alpha modulate lipid metabolism be increasing lipolysis of triglycerides (51,205), an event that would eventually lead to the formation of HDL like apolipoproteins A-I and A-II (51,56,57). Besides its effects on lipid metabolism, agonists of PPAR alpha are known to suppress inflammation (58)(59)(60)(61)(62), modulate the immune response (37,38), improve glucose metabolism (62, 152, 206), mitigate apoptosis/necrosis and relax vascular tissue (143)(144)(145)(146)(147)(148)(149)(150)(151)(152)(153), ameliorate nicotine-induced seizures (207)(208)(209)(210)(211) and neuroprotective in Parkinson's disease (212). Similarly, the PPAR alpha agonist, fenofibrate is cardioprotective and has been shown to inhibit left-ventricular hypertrophy, attenuate abnormalities in left-ventricular relaxation and improve systolic dysfunction in Dahl salt-sensitive hypertensive rats (213).…”