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

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.