title: Diet-induced increase in plasma oxidized LDL promotes early fibrosis in a renal porcine auto-transplantation model.
abstract: BACKGROUND
  In kidney transplantation, the prevalence of hypercholesterolemia as a co-morbidity factor known to affect graft function, is rising due to the increased number of older donors in response to organ shortage as well as to the hyperlipidemic effects of immunosuppressors in recipient. This study aimed to characterize the effects of hypercholesterolemia on renal graft outcome, investigating the role of oxidized low-density lipoprotein (OxLDL).
  
  
  METHODS
  In vivo, we used a porcine preclinical model of renal auto-transplantation modulated by two experimental diets: a normal (n = 6) or a hyperlipidemic diet (n = 5) maintained during the 3 month follow-up after the surgical procedure. Kidney function and OxLDL levels were monitored as well as fibrosis, LOX-1 and TGF beta signaling pathways. In vitro, we used human artery endothelial cells subjected to OxLDL to investigate the TGF beta profibrotic pathway and the role of the scavenger receptor LOX-1.
  
  
  RESULTS
  Hyperlipidemic diet-induced increase in plasma OxLDL levels at the time of surgery correlated with an increase in proteinuria 3 months after transplantation, associated with an early graft fibrosis combined with an activation of renal TGF beta signaling. These data suggest a direct involvement of OxLDL in the hyperlipidemic diet-induced activation of the pro-fibrotic TGF beta pathway which seems to be activated by LOX-1 signaling. These results were supported by studies with endothelial cells incubated in culture medium containing OxLDL promoting TGF beta expression inhibited by LOX-1 antibody.
  
  
  CONCLUSIONS
  These results implicate OxLDL in the hyperlipidemic diet-promoted fibrosis in transplanted kidneys, suggesting LOX-1 as a potential therapeutic target and reinforce the need to control cholesterol levels in kidney transplant recipients.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chatauret
authors.forename: Frédéric
authors.initials: F
authors.lastname: Favreau
authors.forename: Sebastien
authors.initials: S
authors.lastname: Giraud
authors.forename: Antoine
authors.initials: A
authors.lastname: Thierry
authors.forename: Ludivine
authors.initials: L
authors.lastname: Rossard
authors.forename: Sylvain
authors.initials: S
authors.lastname: Le Pape
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
authors.affiliation: INSERM, U1082, Ischémie-reperfusion en transplantation rénale, Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers 86000, France. t.hauet@chu-poitiers.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Hauet
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001158:Arteries / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D023421:Models, Animal; D011507:Proteinuria / Q000097:blood / Q000150:complications / Q000473:pathology; D051131:Receptors, Oxidized LDL / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D034421:Sus scrofa; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014182:Transplantation, Autologous; D014746:Vimentin / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D008077:Lipoproteins, LDL; D051131:Receptors, Oxidized LDL; D016212:Transforming Growth Factor beta; D014746:Vimentin; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D003404:Creatinine