Pretreatment by low-dose fibrates protects against acute free fatty acid-induced renal tubule toxicity by counteracting PPAR{alpha} deterioration

Journal Article · Sun May 01 04:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.02.012· OSTI ID:21535281

Takahashi, Kyoko ^[1]; Kamijo, Yuji ^[1]; Hora, Kazuhiko ^[2]; Hashimoto, Koji ^[1]; Higuchi, Makoto ^[2]; Nakajima, Takero ^[1]; Ehara, Takashi; Shigematsu, Hidekazu ^[3]; Gonzalez, Frank J ^[4]; Aoyama, Toshifumi ^[1]

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1. Department of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621 (Japan)
2. Department of Nephrology Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621 (Japan)
3. Department of Pathology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621 (Japan)
4. Laboratory of Metabolism, National Cancer Institute, Bethesda, MD (United States)

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 (PPAR{alpha}), suggesting the benefit of PPAR{alpha} activation. However, an earlier study using a murine acute tubular injury model, FFA-overload nephropathy, demonstrated that high-dose treatment of PPAR{alpha} agonist (0.5% clofibrate diet) aggravated the tubular damage as a consequence of excess serum accumulation of clofibrate metabolites due to decreased kidney elimination. To induce the renoprotective effects of PPAR{alpha} agonists without drug accumulation, we tried a pretreatment study using low-dose clofibrate (0.1% clofibrate diet) using the same murine model. Low-dose clofibrate pretreatment prevented acute tubular injuries without accumulation of its metabolites. The tubular protective effects appeared to be associated with the counteraction of PPAR{alpha} 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 NF{kappa}B activation. These effects are common to other fibrates and dependent on PPAR{alpha} function. Interestingly, however, clofibrate pretreatment also exerted PPAR{alpha}-independent tubular toxicities in PPAR{alpha}-null mice with FFA-overload nephropathy. The favorable properties of fibrates are evident when PPAR{alpha}-dependent tubular protective effects outweigh their PPAR{alpha}-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 PPAR{alpha} activator that has a steady serum concentration regardless of kidney dysfunction. - Graphical Abstract: Massive proteinuria introduces free fatty acid toxicity to proximal tubular epithelial cells (PTECs). PPAR{alpha} activationvia clofibrate pretreatment maintains fatty acid catabolism and attenuates oxidative stress, apoptosis, and NF{kappa}B activation, resulting in protection of PTECs. The favorable properties of fibrates are evident when PPAR{alpha}-dependent tubular protective effects outweigh their PPAR{alpha}-independent tubular toxicities. Display Omitted Highlights: > Clofibrate pretreatment protects against acute FFA-induced tubular toxicity. > PPAR{alpha} activation decreases FFA influx and maintains fatty acid catabolism. > PPAR{alpha} activation attenuates oxidative stress, apoptosis, and NF{kappa}B activation. > Protective effects must outweigh PPAR{alpha}-independent tubular toxicities of fibrates.

• OSTI ID: 21535281
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 252; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

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60 APPLIED LIFE SCIENCES
ALANINES
AMINO ACIDS
AMINOTRANSFERASES
ANIMALS
APOPTOSIS
BODY
BUILDUP
CARBON COMPOUNDS
CARBON MONOXIDE
CARBON OXIDES
CARBOXYLIC ACIDS
CATABOLISM
CATTLE
CHALCOGENIDES
CHOLESTEROL
DAMAGE
DISEASES
DOMESTIC ANIMALS
DOSES
ENZYMES
ESTERS
GENE AMPLIFICATION
HYDROXY COMPOUNDS
INJURIES
KIDNEYS
LIPIDS
MAMMALS
MEMBRANE PROTEINS
METABOLISM
METABOLITES
MICE
NITROGEN TRANSFERASES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC PHOSPHORUS COMPOUNDS
ORGANS
OXIDES
OXIDOREDUCTASES
OXYGEN COMPOUNDS
PHOSPHOLIPIDS
POLYMERASE CHAIN REACTION
PROTEINS
RECEPTORS
RODENTS
RUMINANTS
STEROIDS
STEROLS
SUPEROXIDE DISMUTASE
TOXICITY
TRANSFERASES
TRIGLYCERIDES
TUBULES
VERTEBRATES