1. Reduced kidney lipoprotein lipase and renal tubule triglyceride accumulation in cisplatin-mediated acute kidney injury.
- Author
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Li S, Nagothu K, Ranganathan G, Ali SM, Shank B, Gokden N, Ayyadevara S, Megyesi J, Olivecrona G, Chugh SS, Kersten S, and Portilla D
- Subjects
- Acute Kidney Injury chemically induced, Acute Kidney Injury enzymology, Adipose Tissue, White drug effects, Adipose Tissue, White pathology, Angiopoietin-Like Protein 4, Angiopoietins biosynthesis, Animals, Azo Compounds, Blotting, Western, Body Weight drug effects, Cell Differentiation drug effects, Cells, Cultured, Coloring Agents, Gene Expression drug effects, Kidney drug effects, Kidney enzymology, Kidney Tubules enzymology, Liver drug effects, Liver metabolism, Male, Membrane Proteins biosynthesis, Mice, Necrosis, Neutrophil Infiltration drug effects, Peroxisome Proliferator-Activated Receptors pharmacology, RNA, Messenger biosynthesis, RNA, Messenger genetics, Receptors, Lipoprotein biosynthesis, Acute Kidney Injury metabolism, Antineoplastic Agents, Cisplatin, Kidney metabolism, Kidney Tubules metabolism, Lipoprotein Lipase metabolism, Triglycerides metabolism
- Abstract
Peroxisome proliferator-activated receptor-α (PPARα) activation attenuates cisplatin (CP)-mediated acute kidney injury by increasing fatty acid oxidation, but mechanisms leading to reduced renal triglyceride (TG) accumulation could also contribute. Here, we investigated the effects of PPARα and CP on expression and enzyme activity of kidney lipoprotein lipase (LPL) as well as on expression of angiopoietin protein-like 4 (Angptl4), glycosylphosphatidylinositol-anchored-HDL-binding protein (GPIHBP1), and lipase maturation factor 1 (Lmf1), which are recognized as important proteins that modulate LPL activity. CP caused a 40% reduction in epididymal white adipose tissue (WAT) mass, with a reduction of LPL expression and activity. CP also reduced kidney LPL expression and activity. Angptl4 mRNA levels were increased by ninefold in liver and kidney tissue and by twofold in adipose tissue of CP-treated mice. Western blots of two-dimensional gel electrophoresis identified increased expression of a neutral pI Angptl4 protein in kidney tissue of CP-treated mice. Immunolocalization studies showed reduced staining of LPL and increased staining of Angptl4 primarily in proximal tubules of CP-treated mice. CP also increased TG accumulation in kidney tissue, which was ameliorated by PPARα ligand. In summary, a PPARα ligand ameliorates CP-mediated nephrotoxicity by increasing LPL activity via increased expression of GPHBP1 and Lmf1 and by reducing expression of Angptl4 protein in the proximal tubule.
- Published
- 2012
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