Mechanism of tacrolimus-induced chronic renal fibrosis following transplantation is regulated by ox-LDL and its receptor, LOX-1

Abstract

Chronic renal allograft dysfunction (CRAD) is the most common cause of graft failure following renal transplantation. However, the underlying mechanisms remain to be fully elucidated. Immunosuppressants and hyperlipidemia are associated with renal fibrosis following long-term use. The present study aimed to determine the effects of tacrolimus (FK506) and lipid metabolism disorder on CRAD. In vitro and in vivo models were used for this investigation. Cells of the mouse proximal renal tubular epithelial cell strain, NRK-52E, were cultured either with oxidized low-density lipoprotein (ox-LDL), FK506, ox-LDL combined with FK506, or vehicle, respectively. Changes in cell morphology and changes in the levels of lectin-like ox-LDL receptor-1 (LOX-1), reactive oxygen species (ROS), hydrogen peroxide and fibrosis-associated genes were evaluated at 24, 48 and 72 h. In separate experiment, total of 60 Sprague-Dawley rats were divided randomly into four groups, which included a high-fat group, FK506 group, high-fat combined with FK506 group, and control group. After 2, 4 and 8 weeks, the serum lipid levels, the levels of ox-LDL, ROS, and the expression levels of transforming growth factor (TGF)-β1 and connective tissue growth factor were determined. The in vitro and in vivo models revealed that lipid metabolism disorder and FK506 caused oxidative stress and a fibrogenic response. In addition, decreased levels of LOX-1 markedly reduced the levels of TGF-β1 in the in vitro model. Taken together, FK506 and dyslipidemia were found to be associated with CRAD following transplantation.

Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis

“…This agrees well with a reduced collagen deposition in atherosclerotic lesions of LOX-1 −/− mice (Hu et al, 2008a). Importantly, the pro-fibrotic activity of LOX-1 is not limited to atherosclerosis, but has also been observed in other disease models (Hu et al, 2009;Lu et al, 2012;Wang et al, 2012;Dai et al, 2014;Deng et al, 2016). It will be of interest if also in these contexts LOX-1 signaling is controlled by SPPL2a/b proteases.…”

Protective Effects of Nargenicin A1 against Tacrolimus-Induced Oxidative Stress in Hirame Natural Embryo Cells

“…Although immunosuppressants are widely used to treat many diseases, long-term treatment may have serious adverse effects, and thus, new strategies are required [31]. In many previous studies, tacrolimus has been shown to cause oxidative stress in various tissues [32,33]. For example, intracellular ROS accumulation has been shown to play a key role in the apoptosis of kidney and renal cells by tacrolimus [16,34], and oxidative stress caused by excessive ROS production also plays a major role in the induction of apoptosis in Jurkat human T lymphocytes [35,36].…”

Interleukin-1β Promotes Ox-LDL Uptake by Human Glomerular Mesangial Cells via LOX-1

“…Increased LOX-1 expression can promote Ox-LDL endocytosis, suggesting that there may be a "malignant" cycle involving Ox-LDL-ROS-LOX-1, subsequently activating nuclear factor-κB and other cytokines to trigger an inflammatory response, which plays a crucial role in acceleration of renal injury. Consequently, LOX-1 combined with Ox-LDL not only promotes uptake of lipids, but also induces expression of inflammatory cytokines such as transforming growth factor-β(TGF-β), which stimulate the proliferation of HMCs and accelerate deterioration of kidney disease, suggesting that LOX-1 plays a key contributing role in progression of glomerulosclerosis [23].…”