title: Inflammatory stress reduces the effectiveness of statins in the kidney by disrupting HMGCoA reductase feedback regulation.
abstract: BACKGROUND
  Patients with chronic kidney disease (CKD) are unlikely to gain the same benefit from conventional doses of statins as do patients with cardiovascular disease alone. This study investigated whether inflammation accompanying CKD causes statin resistance.
  
  
  METHODS
  Inflammatory stress was induced by adding cytokines and lipopolysaccharide (LPS) to human mesangial cells (HMCs) in vitro, and in vivo by subcutaneous casein injection in apolipoprotein E, scavenger receptors class A and CD36 triple knockout mice.
  
  
  RESULTS
  Inflammatory stress exacerbated cholesterol accumulation and was accompanied in vitro and in vivo by increased HMGCoA reductase (HMGCoA-R) mRNA and protein expression mediated via activation of the sterol regulatory element-binding protein cleavage-activating protein (SCAP)/sterol regulatory element-binding protein 2 pathway. Atorvastatin reduced HMGCoA-R enzymatic activity and intracellular cholesterol synthesis in vitro; however, inflammatory stress weakened these suppressive effects. Atorvastatin at concentrations of 15 µM inhibited HMGCoA-R activity by 50% (IC50) in HMCs, but the same concentration in the presence of interleukin (IL)-1β resulted in only 30% inhibition of HMGCoA-R activity in HMCs. Knocking down SCAP prevented statin resistance induced by IL-1β, and overexpression of SCAP-induced statin resistance even without inflammatory stress. In vivo, the amount of atorvastatin required to lower serum cholesterol and decrease kidney lipid accumulation rose from 2 to 10 mg/kg/day in the presence of inflammatory stress.
  
  
  CONCLUSIONS
  Inflammatory stress can disrupt HMGCoA-R-mediated cholesterol synthesis resulting in intracellular lipid accumulation and statin resistance.
authors.affiliation: Centre for Lipid Research, Key Laboratory of Metabolism on Lipid and Glucose, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Centre for Lipid Research, Key Laboratory of Metabolism on Lipid and Glucose, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Centre for Lipid Research, Key Laboratory of Metabolism on Lipid and Glucose, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, University College London, London, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wheeler
authors.affiliation: John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, University College London, London, UK.
authors.forename: Zac
authors.initials: Z
authors.lastname: Varghese
authors.affiliation: John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, University College London, London, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: Moorhead
authors.affiliation: John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, University College London, London, UK.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Powis
authors.affiliation: Centre for Lipid Research, Key Laboratory of Metabolism on Lipid and Glucose, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Xiong Z
authors.initials: XZ
authors.lastname: Ruan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D000069059:Atorvastatin; D015153:Blotting, Western; D018955:CD36 Antigens / Q000502:physiology; D002364:Caseins / Q000008:administration & dosage; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance; D025461:Feedback, Physiological / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001057:Apolipoproteins E; D000069059:Atorvastatin; D018955:CD36 Antigens; D002364:Caseins; D002784:Cholesterol; D016207:Cytokines; D006538:Heptanoic Acids; D006903:Hydroxymethylglutaryl CoA Reductases; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D011758:Pyrroles; D012333:RNA, Messenger; D051782:Sterol Regulatory Element Binding Protein 2; D014409:Tumor Necrosis Factor-alpha; C115472:Cyfip1 protein, mouse
keywords: LDL cholesterol; chronic inflammation; cytokines; statin resistance