title: Endothelial peroxisomal dysfunction and impaired pexophagy promotes oxidative damage in lipopolysaccharide-induced acute kidney injury.
abstract: OBJECTIVE
  We examined that (a) how the endotoxic stress affects peroxisomal function and autophagic degradation of peroxisomes-pexophagy, (b) how a superimposed dysfunction of lysosomes and pexophagy modifies responses to lipopolysaccharide (LPS), and (c) the mechanisms of peroxisomal contribution to renal injury. To accomplish this, we used lysosome-defective Lyst-mice in vivo and primary endothelial cells in vitro, and compared the responses with wild-type (WT) littermates.
  
  
  RESULTS
  LPS induced pexophagic degradation, followed by proliferation of peroxisomes in WT mice, which was abolished in Lyst-mice. Lyst-mice exhibited impaired activation of catalase, which together with preserved hydrogen peroxide-generating β-oxidation resulted in redox disequilibrium. LPS treatment induced a heightened inflammatory response, increased oxidative damage, and aggravated renal injury in Lyst-mice. Similarly, as in vivo, LPS-activated lysosomal (LYS) pexophagy and transiently repressed peroxisomes in vitro, supported by reduced peroxisomal density in the vicinity of lysosomes. Peroxisomal dynamics was also abolished in lysosome-defective cells, which accumulated peroxisomes with compromised functions and intraorganellar redox imbalance.
  
  
  METHODS
  We demonstrated that pexophagy is a default response to endotoxic injury. However, when LYS dysfunction (a frequent companion of chronic diseases) is superimposed, recycling and functioning of peroxisomes are impaired, and an imbalance between hydrogen peroxide-generating β-oxidation and hydrogen peroxide-detoxifying catalase ensues, which ultimately results in peroxisomal burnout.
  
  
  CONCLUSIONS
  Our data strongly suggest that pexophagy, a cellular mechanism per se, is essential in functional maintenance of peroxisomes during LPS exposure. Inhibition of pexophagy results in accumulation of impaired peroxisomes, redox disequilibrium, and aggravated renal damage.
authors.affiliation: Department of Medicine, New York Medical College, Valhalla, New York 10595, USA. vaskorad@gmail.com
authors.forename: Radovan
authors.initials: R
authors.lastname: Vasko
authors.forename: Brian B
authors.initials: BB
authors.lastname: Ratliff
authors.forename: Stefan
authors.initials: S
authors.lastname: Bohr
authors.forename: Ellen
authors.initials: E
authors.lastname: Nadel
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Sandhya
authors.initials: S
authors.lastname: Xavier
authors.forename: Praveen
authors.initials: P
authors.lastname: Chander
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goligorsky
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism*; D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000419:Albuminuria; D000818:Animals; D001343:Autophagy; D002374:Catalase / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood; D008070:Lipopolysaccharides / Q000009:adverse effects; D051379:Mice; D008954:Models, Biological; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D020675:Peroxisomes / Q000378:metabolism*; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; C490981:Gtf2h1 protein, mouse; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; D006861:Hydrogen Peroxide; D002374:Catalase; D042962:Acyl-CoA Oxidase