Abstract
Activation of the farnesoid X receptor (FXR) has indicated a therapeutic potential for this nuclear bile acid receptor in the prevention of diabetic nephropathy and obesity-induced renal damage. Here, we investigated the protective role of FXR against kidney damage induced by obesity in mice that had undergone uninephrectomy, a model resembling the clinical situation of kidney donation by obese individuals. Mice fed a high-fat diet developed the core features of metabolic syndrome, with subsequent renal lipid accumulation and renal injury, including glomerulosclerosis, interstitial fibrosis, and albuminuria. The effects were accentuated by uninephrectomy. In human renal biopsies, staining of 4-hydroxynonenal (4-HNE), glucose-regulated protein 78 (GRP78) and C/EBP-homologous protein (CHOP), markers of ER stress, was more prominent in the proximal tubules of 15 obese compared with 16 non-obese patients. In mice treated with the FXR agonist obeticholic acid (OCA), renal injury, renal lipid accumulation, apoptosis and changes in lipid peroxidation were attenuated. Moreover, disturbed mitochondrial function was ameliorated and the mitochondrial respiratory chain recovered following OCA treatment. Culturing renal proximal tubular cells with free fatty acid (FFA) and FXR agonists showed that FXR activation protected cells from FFA-induced oxidative stress and ER stress, as denoted by a reduction in the level of ROS staining and Grp78 immunostaining, respectively. Several genes involved in glutathione metabolism were induced by FXR activation in the remnant kidney, which was consistent with a decreased glutathione disulfide / glutathione ratio. In summary, FXR activation maintains endogenous glutathione homeostasis and protects the kidney in uninephrectomized mice from obesity-induced injury.
Gai, Zhibo