title: Hyperlipidemia-associated renal damage decreases Klotho expression in kidneys from ApoE knockout mice.
abstract: BACKGROUND
  Klotho is a renal protein with anti-aging properties that is downregulated in conditions related to kidney injury. Hyperlipidemia accelerates the progression of renal damage, but the mechanisms of the deleterious effects of hyperlipidemia remain unclear.
  
  
  METHODS
  We evaluated whether hyperlipidemia modulates Klotho expression in kidneys from C57BL/6 and hyperlipidemic apolipoprotein E knockout (ApoE KO) mice fed with a normal chow diet (ND) or a Western-type high cholesterol-fat diet (HC) for 5 to 10 weeks, respectively.
  
  
  RESULTS
  In ApoE KO mice, the HC diet increased serum and renal cholesterol levels, kidney injury severity, kidney macrophage infiltration and inflammatory chemokine expression. A significant reduction in Klotho mRNA and protein expression was observed in kidneys from hypercholesteromic ApoE KO mice fed a HC diet as compared with controls, both at 5 and 10 weeks. In order to study the mechanism involved in Klotho down-regulation, murine tubular epithelial cells were treated with ox-LDL. Oxidized-LDL were effectively uptaken by tubular cells and decreased both Klotho mRNA and protein expression in a time- and dose-dependent manner in these cells. Finally, NF-κB and ERK inhibitors prevented ox-LDL-induced Klotho downregulation.
  
  
  CONCLUSIONS
  Our results suggest that hyperlipidemia-associated kidney injury decreases renal expression of Klotho. Therefore, Klotho could be a key element explaining the relationship between hyperlipidemia and aging with renal disease.
authors.affiliation: Vascular and Renal Research Lab, IIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sastre
authors.affiliation: Vascular and Renal Research Lab, IIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Rubio-Navarro
authors.affiliation: Vascular and Renal Research Lab, IIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Buendía
authors.affiliation: Vascular and Renal Research Lab, IIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gómez-Guerrero
authors.affiliation: Hospital Clinico San Carlos, Madrid, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Blanco
authors.affiliation: Vascular and Renal Research Lab, IIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mas
authors.affiliation: Vascular and Renal Research Lab, IIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain ; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.affiliation: Vascular and Renal Research Lab, IIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
authors.affiliation: Vascular and Renal Research Lab, IIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Vascular and Renal Research Lab, IIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Moreno
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D006949:Hyperlipidemias / Q000150:complications* / Q000235:genetics*; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology*; D000090265:Klotho Proteins; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D005966:Glucuronidase; D000090265:Klotho Proteins