title: Reduced kidney lipoprotein lipase and renal tubule triglyceride accumulation in cisplatin-mediated acute kidney injury.
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.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
authors.forename: Shenyang
authors.initials: S
authors.lastname: Li
authors.forename: Kiran
authors.initials: K
authors.lastname: Nagothu
authors.forename: Gouri
authors.initials: G
authors.lastname: Ranganathan
authors.forename: Syed M
authors.initials: SM
authors.lastname: Ali
authors.forename: Brian
authors.initials: B
authors.lastname: Shank
authors.forename: Neriman
authors.initials: N
authors.lastname: Gokden
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ayyadevara
authors.forename: Judit
authors.initials: J
authors.lastname: Megyesi
authors.forename: Gunilla
authors.initials: G
authors.lastname: Olivecrona
authors.forename: Sumant S
authors.initials: SS
authors.lastname: Chugh
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.forename: Didier
authors.initials: D
authors.lastname: Portilla
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000187:drug effects / Q000473:pathology; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents; D001391:Azo Compounds; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin; D004396:Coloring Agents; D015870:Gene Expression / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D007684:Kidney Tubules / Q000201:enzymology / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D009336:Necrosis; D020556:Neutrophil Infiltration / Q000187:drug effects; D047492:Peroxisome Proliferator-Activated Receptors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018110:Receptors, Lipoprotein / Q000096:biosynthesis; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D000970:Antineoplastic Agents; D001391:Azo Compounds; D004396:Coloring Agents; C472779:GPI-HBP1 protein, mouse; C546367:LMF1 protein, mouse; D008565:Membrane Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D018110:Receptors, Lipoprotein; D014280:Triglycerides; D008071:Lipoprotein Lipase; C011049:oil red O; D002945:Cisplatin