Cell Biology – Immunology – Pathology
Kidney International (2005) 68, 2680–2693; doi:10.1111/j.1523-1755.2005.00739.x
Fibrate prevents cisplatin-induced proximal tubule cell death
KIRAN K NAGOTHU*, RENU BHATT*, GUR P KAUSHAL* and DIDIER PORTILLA*
*Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
Correspondence: Didier Portilla, M.D., University of Arkansas for Medical Sciences, Department of Medicine, Slot 501, 4301 W. Markham, St. Little Rock AR 72205. E-mail:portilladidier@uams.edu
Received 11 March 2005; Revised 20 May 2005; Re-revised 1 July 2005; Accepted 20 July 2005.
Abstract
Fibrate prevents cisplatin-induced proximal tubule cell death.
Background
In previous studies we have shown that cisplatin inhibits peroxisome proliferator-activated receptor-
(PPAR-) activity and consequently fatty acid oxidation, and these events precede proximal tubule cell death. In addition the use of fibrate class of PPAR- ligands ameliorate renal function by preventing both inhibition of fatty acid oxidation and proximal tubule cell death.
Methods
LLC-PK1 cells were treated with cisplatin and apoptosis was established by the presence of nuclear fragmentation and by cell cycle analysis. Proximal tubular cells treated with cisplatin and bezafibrate were subjected to sub cellular fractionation and the presence of Bax, Bcl-2, cytochrome c, and active caspase-3 in the cytosolic and mitochondrial membrane fractions was determined by Western blot analysis. PPAR- activity was measured by determining luciferase activity after transfection of LLC-PK1 cells with TK-Luc 3
PPAR response elements (PPRE), and the accumulation of nonesterified free fatty acids was measured in lysates obtained from cells treated with cisplatin and bezafibrate.
Results
Incubation of LLC-PK1 cells with 25 
mol/L cisplatin for 18 hours induced 41.5% apoptosis measured by cell cycle analysis. Cisplatin-induced apoptosis was significantly suppressed by bezafibrate, a fibrate class of PPAR- ligand. Bezafibrate treatment of LLC-PK1 cells prevented cisplatin-induced translocation of proapoptotic Bax from the cytosol to the mitochondrial fraction, and increased the expression of antiapoptotic molecule Bcl-2. Cisplatin-induced inhibition of PPAR- activity was accompanied by increased accumulation of nonesterified free fatty acids. Pretreatment with bezafibrate prevented both the inhibition of PPAR- activity and the accumulation of nonesterified free fatty acids induced by cisplatin. Finally, bezafibrate prevented cisplatin-induced release of cytochrome c from the mitochondria to the cytosol, and the cleavage of procaspase-3 to active caspase-3.
Conclusion
Bezafibrate treatment inhibits cisplatin-mediated tubular injury by preventing the activation of various cellular mechanisms that lead to proximal tubule cell death. These findings support our previous observations where the use of fibrates represents a novel strategy to ameliorate proximal tubule cell death in cisplatin-induced acute renal failure.
Keywords:
peroxisome proliferator activated receptor-alpha, nonesterified fatty acids, apoptosis, renal proximal tubular epithelial cells
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