A role of liver fatty acid-binding protein in cisplatin-induced acute renal failure.
Previous studies from our laboratory showed that increased fatty acid oxidation by the kidney is cytoprotective during cisplatin (CP)-mediated nephrotoxicity. In this study, we determined the effects of CP and fibrates on peroxisome proliferation and the expression of liver fatty acid-binding protein (L-FABP) in normal mice, and in mice transgenically overexpressing human L-FABP (h-L-FABP). Labeling of peroxisomes demonstrated reduced peroxisomal staining in the proximal tubule of CP-treated mice compared with control mice. There was increased peroxisomal labeling in the proximal tubules of both control and CP-treated mice when either was treated with fibrate; a known peroxisome proliferator-activated receptor-alpha ligand. L-FABP protein expression, not detected in control or CP-treated mice, was significantly increased in the proximal tubules of fibrate-treated mice of either group. In the transgenic mice, CP increased the shedding of h-L-FABP in the urine, which was decreased by fibrate as was the acute renal failure. A cytosolic pattern of h-L-FABP expression was found in the proximal tubules of untreated transgenic mice with a nuclear presence in CP-treated mice. Fibrate pretreatment restored the cytosolic expression pattern in CP-treated mice. Our study shows that fibrate may improve CP-induced acute renal failure due to both peroxisome proliferation and increased L-FABP in the cytosol of the proximal tubule.
Negishi
K
K
Department of Nephrology and Endocrinology, University of Tokyo, Tokyo, Japan.
Noiri
E
E
Sugaya
T
T
Li
S
S
Megyesi
J
J
Nagothu
K
K
Portilla
D
D
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002945:Cisplatin; D003404:Creatinine / Q000097:blood; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D020675:Peroxisomes / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; C493319:FABP1 protein, human; C493320:Fabp1 protein, mouse; D050556:Fatty Acid-Binding Proteins; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; C006253:pirinixic acid; D003404:Creatinine; D002945:Cisplatin