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Pretreatment by low-dose fibrates protects against acutefree fatty acid-induced renal tubule toxicity by counteracting PPARα deterioration.
MedLine Citation:
PMID:  21338618     Owner:  NLM     Status:  Publisher    
Development of a preventive strategy against tubular damage associated with proteinuria is of great importance. Recently, free fatty acid(FFA) toxicities accompanying proteinuria were found to be a main cause of tubular damage, which was aggravated by insufficiency of peroxisome proliferator-activated receptor alpha (PPARα),suggesting the benefit ofPPARαactivation.However, an earlier study using a murine acute tubular injurymodel, FFA-overloadnephropathy,demonstrated that high-dose treatment of PPARα agonist (0.5 % clofibrate diet)aggravatedthe tubular damageas a consequence ofexcess serum accumulation of clofibrate metabolites due to decreasedkidneyelimination. To induce the renoprotective effects of PPARα agonists without drug accumulation, we tried a pretreatment study using low-dose clofibrate (0.1 % clofibrate diet)using the same murinemodel.Low-doseclofibrate pretreatment prevented acute tubular injuries without accumulation of its metabolites. The tubular protective effects appeared to be associated with the counteraction of PPARα deterioration, resulting in the decrease of FFAs influx to the kidney, maintenance of fatty acid oxidation, diminution of intracellular accumulation of undigested FFAs, and attenuation of disease developmental factors including oxidative stress, apoptosis, and NFκB activation. These effects are common to other fibrates and dependent on PPARα function. Interestingly, however, clofibrate pretreatment also exerted PPARα-independent tubular toxicities in PPARα-null mice with FFA-overload nephropathy. The favorable properties of fibrates are evident when PPARα-dependent tubular protective effects outweigh their PPARα-independent tubular toxicities. This delicate balance seems to be easily affected by the drug dose. It will be important to establish the appropriate dosage of fibrates for treatment against kidney disease and to develop a novel PPARα activator that has a steady serum concentration regardless of kidney dysfunction.
Kyoko Takahashi; Yuji Kamijo; Kazuhiko Hora; Koji Hashimoto; Makoto Higuchi; Takero Nakajima; Takashi Ehara; Hidekazu Shigematsu; Frank J Gonzalez; Toshifumi Aoyama
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-2-18
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  -     ISSN:  1096-0333     ISO Abbreviation:  -     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-2-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier Inc.
Department of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu University School of Medicine,3-1-1 Asahi, Matsumoto, 390-8621, Japan; Department of Nephrology Internal Medicine, Shinshu University School of Medicine,3-1-1 Asahi, Matsumoto, 390-8621, Japan.
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