Diet-induced increase in plasma oxidized LDL promotes early fibrosis in a renal porcine auto-transplantation model

Nicolas Chatauret, Frédéric Favreau, Sebastien Giraud, Antoine Thierry, Ludivine Rossard, Sylvain Le Pape, Lilach O Lerman, Thierry Hauet

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Article number76
JournalJournal of Translational Medicine
Volume12
Issue number1
DOIs
StatePublished - Mar 22 2014

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Nutrition
Fibrosis
Swine
Transplantation
Diet
Kidney
Plasmas
Transforming Growth Factor beta
Grafts
Endothelial cells
Hypercholesterolemia
Transplants
Kidney Transplantation
Endothelial Cells
Chemical activation
Transplantation (surgical)
Transforming Growth Factor beta1
Scavenger Receptors
oxidized low density lipoprotein
Proteinuria

Keywords

  • Extracellular matrix
  • Hypercholesterolemia
  • Ischemia reperfusion
  • Kidney transplantation
  • Oxidized LDL
  • Preclinical model

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Diet-induced increase in plasma oxidized LDL promotes early fibrosis in a renal porcine auto-transplantation model. / Chatauret, Nicolas; Favreau, Frédéric; Giraud, Sebastien; Thierry, Antoine; Rossard, Ludivine; Le Pape, Sylvain; Lerman, Lilach O; Hauet, Thierry.

In: Journal of Translational Medicine, Vol. 12, No. 1, 76, 22.03.2014.

Research output: Contribution to journalArticle

Chatauret, Nicolas ; Favreau, Frédéric ; Giraud, Sebastien ; Thierry, Antoine ; Rossard, Ludivine ; Le Pape, Sylvain ; Lerman, Lilach O ; Hauet, Thierry. / Diet-induced increase in plasma oxidized LDL promotes early fibrosis in a renal porcine auto-transplantation model. In: Journal of Translational Medicine. 2014 ; Vol. 12, No. 1.
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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.",
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T1 - Diet-induced increase in plasma oxidized LDL promotes early fibrosis in a renal porcine auto-transplantation model

AU - Chatauret, Nicolas

AU - Favreau, Frédéric

AU - Giraud, Sebastien

AU - Thierry, Antoine

AU - Rossard, Ludivine

AU - Le Pape, Sylvain

AU - Lerman, Lilach O

AU - Hauet, Thierry

PY - 2014/3/22

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N2 - 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.

AB - 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.

KW - Extracellular matrix

KW - Hypercholesterolemia

KW - Ischemia reperfusion

KW - Kidney transplantation

KW - Oxidized LDL

KW - Preclinical model

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