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

Journal of Translational Medicine

Thierry Hauet⁴  Lilach O Lerman³  Sylvain Le Pape¹  Ludivine Rossard¹  Antoine Thierry¹  Sebastien Giraud⁴  Frédéric Favreau⁴  Nicolas Chatauret² 

[1] INSERM, U1082, Ischémie-reperfusion en transplantation rénale, Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers 86000, France;CHU de Poitiers, Laboratoire de biochimie, Poitiers 86000, France;Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota 55905, USA;INRA, UE1372 GenESI, Plateforme Ibisa, Surgères, France

关键词: Extracellular matrix;    Preclinical model;    Kidney transplantation;    Ischemia reperfusion;    Oxidized LDL;    Hypercholesterolemia;   

Others  :  817488
DOI  :  10.1186/1479-5876-12-76

 received in 2013-09-05, accepted in 2014-03-12,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Chatauret et al.; licensee BioMed Central Ltd.

【 图 表 】

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